High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions

ABSTRACT

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) for treatment of pulmonary conditions (e.g. asthma). The HPCs/HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPCs/HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of International PatentApplication No. PCT/CN2013/072693, filed Mar. 15, 2013, which claimspriority to Chinese Patent Application No. 20121015155.7, filed May 16,2012, which is incorporated herein by reference in its entirety, as iffully set forth herein.

FIELD OF THE INVENTION

This invention relates to the field of pharmaceutical compositionscapable of penetrating one or more biological barriers and methods ofusing the pharmaceutical compositions for preventing and/or treatingpulmonary conditions (e.g. asthma, lower, and upper respiratory tractinfections) in humans and animals. The invention also relates to methodsof using the pharmaceutical compositions for screening new drugcandidates.

BACKGROUND OF THE INVENTION

Pulmonary conditions may be caused by allergy, inflammation, bacterialinfections, or a combination thereof. For example, asthma is a chronicinflammatory condition of the respiratory tract (airway) characterizedby airflow obstruction and bronchospasm. Asthma can be classified as avariable and partially reversible obstruction to air flow involving anoverdeveloped mucus gland, airway thickening due to scarring andinflammation, and bronchoconstriction. Bronchoconstriction is caused byedema and swelling which may be triggered by an immune response toallergens. Bacterial infections of the upper respiratory tract infectioncan also worsen asthmatic symptoms.

The airway of an asthmatic or a subject that is experiencing a chronicpulmonary condition (e.g. emphysema and chronic bronchitis) may bethickened due to scaring and inflammation. Therefore, a need exists inthe art for novel compositions that are capable of efficient andeffective delivery to the action site of a pulmonary condition (e.g.,asthma, lower, and upper respiratory tract infections) of a subject toprevent, reduce or treat conditions as well as minimize adverse sideeffects.

DETAILED DESCRIPTION OF THE INVENTION I. Structures of High PenetrationProdrug (HPP) or High Penetration Composition (HPC)

One aspect of the invention is directed to a high penetration prodrug(HPP) or a high penetration composition (HPC). The term “highpenetration prodrug” or “HPP” or “high penetration composition” or “HPC”as used herein refers to a composition comprising a functional unitcovalently linked to a transportational unit through a linker.

Functional Unit

A functional unit of an HPP or HPC which comprises a moiety of a parentdrug has the properties of: 1) the delivery of the parent drug or theHPP/HPC into a biological subject and/or the transportation of theparent drug across one or more biological barriers are/is desired, 2)the HPP/HPC is capable of penetrating or crossing one or more biologicalbarriers, and 3) the HPP/HPC is capable of being cleaved so as to turnthe moiety of a parent drug into the parent drug or a metabolite of theparent drug.

In certain embodiments, a functional unit may be hydrophilic,lipophilic, or amphiphilic (hydrophilic and lipophilic). The lipophilicmoiety of the functional unit may be inherent or achieved by convertingone or more hydrophilic moieties of the functional unit to lipophilicmoieties. For example, a lipophilic moiety of a functional unit isproduced by converting one or more hydrophilic groups of the functionalunit to lipophilic groups via organic synthesis. Examples of hydrophilicgroups include, without limitation, carboxylic, hydroxyl, thiol, amine,phosphate/phosphonate, guanidine and carbonyl groups. Lipophilicmoieties produced via the modification of these hydrophilic groupsinclude, without limitation, ethers, thioethers, esters, thioesters,carbonates, carbamates, amides, phosphates and oximes. In certainembodiments, a functional unit is converted to a more lipophilic moietythrough acetylation or acylation(alkanoylation). In certain embodiments,a functional unit is converted to a more lipophilic moiety viaesterification.

In certain embodiments, a parent drug of an HPP or HPC is a drug thatcan be used by itself or in combination with other drug(s) to treatpulmonary conditions (e.g. asthma, lower, and upper respiratory tractinfections, chronic bronchitis, chronic obstructive pulmonary disease,emphysema, cystic fibrosis, pneumonia, sarcoidosis, and pulmonaryfibrosis) or a related compound thereof. A related compound of a parentdrug is a compound comprising the structure of the parent drug, ametabolite of the parent drug, or an agent that can be metabolized intothe parent drug or a metabolite of the parent drug after an HPP or HPCpenetrates one or more biological barriers. A related compound of aparent drug further includes a compound that is an analog or mimic ofthe parent drug or a metabolite of the parent drug, or an agent that canbe metabolized into an analog or mimic of the parent drug or ametabolite of the parent drug, after an HPP or HPC penetrates one ormore biological barriers.

The moiety of a parent drug or the related compound thereof can befurther converted to a lipophilic moiety as described supra. The mainclasses of drugs that can be used to treat pulmonary conditions (e.g.asthma, lower, and upper respiratory tract infections, chronicbronchitis, chronic obstructive pulmonary disease, emphysema, cysticfibrosis, pneumonia, sarcoidosis, and pulmonary fibrosis) include, forexample, antihistamines, β2-adrenergic receptor agonists,5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenaseinhibitors, leukotriene receptor antagonists, anti-inflammatory drugs,cough suppressants, decongestants, and antibiotics.

Examples of 5-lipoxygenase-activating protein (FLAP) inhibitors include,without limitation, MK-886[3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoicacid], MK-0591[3-(1-(4-chlorobenzyl-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl))-2,2-dimethylpropanoic acid], 2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]aceticacid, and3-[[1-(4-chlorobenzyl)-4-methyl-6-(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropanoicacid.

Examples of 5-lipoxygenase inhibitors include without limitation,zileuton [(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-hydroxyurea],theophylline [1,3-dimethyl-7H-purine-2,6-dione],2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol,2,6-dimethyl-4-[2-(3-pyridyl)ethenyl]phenol, and2,6-dimethyl-4-[2-(2-thienyl)ethenyl]phenol.

Examples of leukotriene receptor antagonists include, withoutlimitation, montelukast{R-(E)-1-[[[-1-[3-[2-(7-chloro2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneaceticacid},7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylicacid,(E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-dimethylamino]-3-oxopropyl]thio]methyl]thio]propanoicacid sodium salt,2(S)-hydroxyl-3(R)-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoicacid,4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxo-butanoicacid, and3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoicacid.

Examples of antihistamines include, without limitation, fexofenadine((RS)-2-[4-[1-Hydroxy-4-[4-(hydroxy-diphenyl-methyl)-1-piperidyl]butyl]phenyl]-2-methyl-propanoicacid), clemastine((2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine),diphenhydramine (2-(diphenylmethoxy)-N,N-dimethylethanamine),doxylamine[(RS)—N,N-dimethyl-2-(1-phenyl-1-pyridine-2-yl-ethoxy)-ethanamine],desloratadine[8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine],Brompheniramine(3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine),chlorophenamine[3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine,pheniramine, fluorpheniramine, dexchlorpheniramine (Polaramine),deschlorpheniramine, dipheniramine, iodopheniramine, Cromoglicic acid(5,5′-(2-hydroxypropane-1,3-diyl)bis(oxy)bis(4-oxo-4H-chromene-2-carboxylicacid), Loratadine [Ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-piperidinecarboxylate,acrivastine[(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoicacid], ebastine[4-(4-benzhydryloxy-1-piperidyl)-1-(4-tert-butylphenyl)butan-1-one],carebastine, promethazine[(RS)—N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine], andolopatadine[{(11Z)-11-[3-(dimethylamino)-propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}aceticacid].

Examples of β2-adrenergic receptor agonists include, without limitation,albuterol[(RS)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol],levosalbuterol[4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol],terbutaline[(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol],pirbuterol[(RS)-6-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)pyridin-3-ol],procaterol[(±)-(1R,2S)-rel-8-Hydroxy-5-[1-hydroxy-2-(isopropylamino)butyl]-quinolin-2(1H)-one],metaproterenol[(RS)-5-[1-hydroxy-2-(isopropylamino)ethyl]benzene-1,3-diol], fenoterol[(RR,SS)-5-(1-hydroxy-2-{[2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)benzene-1,3-diol],bitolterol mesylate[(RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl]4-methylbenzoate],ritodrine[4-((1R,2S)-1-hydroxy-2-{[2-(4-hydroxyphenyl)ethyl]amino}propyl)phenol],salmeterol[(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxyl)hexylamino]ethyl}phenol],formoterol[(RS,SR)—N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide],bambuterol [(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diylbis(dimethylcarbamate)], clenbuterol[(RS)-1-(4-amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethanol], andindacaterol[(R)-5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one].

Examples of anti-inflammatory drugs include, without limitation,non-steroid anti-inflammatory agents (“NSAIAs,” e.g. aspirin, ibuprofen,diflunisal, and diclofenac).

Examples of cough suppressants include, without limitation,dextromethorphan ((+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan),tipepidine (3-(di-2-thienylmethylene)-1-methylpiperidine), cloperastine(1-[2-[(4-chlorophenyl)-phenyl-methoxy]ethyl]piperidine), benproperine(1-[2-(2-benzylphenoxy)-1-methylethyl]piperidine), dioxopromethazine(9,9-dioxopromethazine), promolate(2-morpholinoethyl-2-phenoxy-2-methylpropionate), fominoben(N-2-chloro-6-benzoyl-aminobenzyl-methylaminoacetyl-morpholine), andpentoxyverine (2-[2-(diethylamino)ethoxy]ethyl1-phenylcyclopentanecarboxylate).

Examples of decongestants include, without limitation, ephedrine [(R,S)-2-(methylamino)-1-phenylpropan-1-ol], levomethamphetamine[(R)—N-methyl-1-phenyl-propan-2-amine], phenylephrine[(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol], propylhexedrine[(RS)—N,α-dimethyl-cyclohexylethylamine], pseudoephedrine[(R*,R*)-2-methylamino-1-phenylpropan-1-ol], synephrine[4-[1-hydroxy-2-(methylamino)ethyl]phenol], and tetrahydrozoline[(RS)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole].

Examples of antibiotics include, without limitation, beta-lactamantibiotics, sulfonamides and quinolones. Examples of beta-lactamantibiotics include, but are not limited to, penicillin derivatives,cephalosporins, penems, monobactams, carbapenems, beta-lactamaseinhibitors and combinations thereof. Examples of penicillin derivativesinclude, but are not limited to, aminopenicillins (e.g. amoxicillin,ampicillin, and epicillin); carboxypenicillins (e.g. carbenicillin,ticarcillin, and temocillin); ureidopenicillins (e.g. azlocillin,piperacillin and mezlocillin); mecillinam, sulbenicillin, benzathinepenicillin, penicillin G (benzylpenicillin), penicillin V(phenoxymethylpenicillin), penicillin O(allylmercaptomethylpenicillinic), procaine penicillin, oxacillin,methicillin, nafcillin, cloxacillin, dicloxacillin, flucloxacillin,pivampicillin, hetacillin, becampicillin, metampicillin, talampicillin,co-amoxiclav (amoxicillin plus clavulanic acid), and piperacillion.Examples of cephalosporins include, but are not limited to, cephalexin,cephalothin, cefazolin, cefaclor, cefuroxime, cefamandole, cefotetan,cefoxitin, ceforanide, ceftriaxone, cefotaxime, cefpodoxime proxetil,ceftazidime, cefepime, cefoperazone, ceftizoxime, cefixime andcefpirome. Examples of penems include, without limitation, faropenem.Examples of monobactams include, without limitation, aztreonam andtigemonam. Examples of carbapenems include, but are not limited to,biapenem, ⋅doripenem, ertapenem, ⋅imipenem, ⋅meropenem, ⋅and panipenem.Examples of beta-lactamase inhibitors include, but are not limited to,tazobactam([2S-(2alpha,3beta,5alpha)]-3-Methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 4,4-dioxide sodium salt), sulbactam(2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid 4,4-dioxide sodium), and clavulanic acid((2R,5R,Z)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylicacid). Other examples of antibiotics include, without limitation,[(N-benzyloxycarbonylamino)methyl]-phosphonic acid mono-(4-nitrophenyl)ester sodium salt, [(N-benzyloxycarbonylamino)methyl]-phosphonic acidmono-(3-pyridinyl) ester sodium salt, sulfanilamide(4-aminobenzenesulfonamide), sulfasalazine(6-oxo-3-(2-[4-(N-pyridin-2-ylsulfamoyl)phenyl]hydrazono)cyclohexa-1,4-dienecarboxylicacid),1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-quinoline-3-carboxylicacid, and nalidixic acid(1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acid).

Examples of sulfonamides include, without limitation, sulfaisodimidine,sulfanilamide, sulfadiazine, sulfisoxazole, sulfamethoxazole,sulfadimethoxine, sulfamethoxypyridazine, sulfacetamide, sulfadoxine,acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide,hydrochlorothiazide, indapamide, mefruside, metolazone, xipamide,dichlorphenamide, dorzolamide, acetazolamide, ethoxzolamide, sultiame,zonisamide, mafenide, celecoxib, darunavir, probenecid, sulfasalazine,and sumatriptan.

Examples of quinolones include, without limitation, cinoxacin,flumequine, nalidixic acid, oxolinic acid, piromidic acid, pipemidicacid, rosoxacin, ciprofloxacin, enoxacin, fleroxacin, lomefloxacin,nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin,balofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin,pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin,gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin,ecinofloxacin, delafloxacin and nalidixic acid.

Transportational Unit

A transportational unit of an HPP comprises a protonatable amine groupthat is capable of facilitating the transportation or crossing of theHPP through one or more biological barriers (e.g., >about 20times, >about 50 times, >about 100 times, >about 300 times, >about 500times, >about 1,000 times or more faster than the parent drug). Incertain embodiments, the protonatable amine group is substantiallyprotonated at a physiological pH. In certain embodiments, the aminegroup can be reversibly protonated. In certain embodiments, atransportational unit may or may not be cleaved from the functional unitafter the penetration of HPP through one or more biological barriers.

In certain embodiments, a functional unit may also contain one or moretransportational units, especially for parent drugs that have at least afree amino group. In certain embodiments, when a functional unitcontains one or more transportational units, the functional unit ismodified such that only one or two amine groups are protobatable. Incertain embodiments, a functional unit contains one or two amine groups.These functional units can be modified or can be used as HPCs withoutfurther modifications. Examples of compounds that have one or two aminegroups include, without limitation, pheniramine, fluorpheniramine,chlorpheniramine, dexchlorpheniramine (Polaramine), deschlorpheniramine,dipheniramine, iodopheniramine, albuterol, levoalbuterol, pirbuterol,procaterol, bitolterol mesylate, ritodrine, salmeterol, formoterol,bambuterol, clenbuterol, and indacaterol.

In certain embodiments, the protonatable amine group is selected fromthe group consisting of pharmaceutically acceptable substituted andunsubstituted amine groups, Structure W-1, Structure W-2, Structure W-3,Structure W-4, Structure W-5, Structure W-6, Structure W-7, StructureW-8, Structure W-9, Structure W-10, Structure W-11, Structure W-12,Structure W-13, Structure W-14, Structure W-15, Structure W-16,Structure W-17 and Structure W-18:

including stereoisomers and pharmaceutically acceptable salts thereof.

Unless otherwise specified, HA is selected from the group consisting ofnothing, and pharmaceutically acceptable acid, e.g. hydrochloridehydrobromide, hydroiodide, nitric acid, sulfic acid, bisulfic acid,phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid,acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid,pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleicacid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid,saccharic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid,p-toluenesulfonic acid and pamoic acid;

-   -   R is selected from the group consisting of nothing, CH₂C(═O)OR₆,        substituted and unsubstituted alkyl, substituted and        unsubstituted cycloalkyl, substituted and unsubstituted        heterocycloalkyl, substituted and unsubstituted alkoxyl,        substituted and unsubstituted perfluoroalkyl, substituted and        unsubstituted alkyl halide, substituted and unsubstituted        alkenyl, substituted and unsubstituted alkynyl, substituted and        unsubstituted aryl, and substituted and unsubstituted        heteroaryl, wherein any CH₂ in R may be further replaced with O,        S, P, NR₆, or any other pharmaceutically acceptable groups;    -   R₆ is independently selected from the group consisting of H, F,        Cl, Br, Na⁺, K⁺, C(═O)R₅, 2-oxo-1-imidazolidinyl, phenyl,        5-indanyl, 2,3-dihydro-1H-inden-5-yl,        4-hydroxy-1,5-naphthyridin-3-yl, substituted and unsubstituted        alkyl, substituted and unsubstituted cycloalkyl, substituted and        unsubstituted heterocycloalkyl, substituted and unsubstituted        alkenyl, substituted and unsubstituted alkynyl, substituted and        unsubstituted alkyloxyl, substituted and unsubstituted        cycloalkyloxyl, substituted and unsubstituted aryl, substituted        and unsubstituted heteroaryl, —C(═O)—W, -L₁-L₄-L₂-W, and W;    -   R₅ is independently selected from the group consisting of H,        C(═O)NH₂, CH₂CH₂OR₆, CH₂CH₂N(CH₃)₂, CH₂CH₂N(CH₂CH₃)₂, Cl, F, Br,        I, substituted and unsubstituted alkyl, substituted and        unsubstituted cycloalkyl, substituted and unsubstituted        heterocycloalkyl, substituted and unsubstituted alkyloxyl,        substituted and unsubstituted cycloalkyloxyl, substituted and        unsubstituted aryl, substituted and unsubstituted heteroaryl,        substituted and unsubstituted alkylcarbonyl, substituted and        unsubstituted alkylamino, —C(═O)—W, L₁-L₄-L₂-W, and W;    -   L₁ being selected from the group consisting of nothing, O, S,        —O-L₃-, —S-L₃-, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-,        —O—CH₂—O—, —O—CH(L₃)-O, and —S—CH(L₃)-O—;    -   L₂ being selected from the group consisting of nothing, O, S,        —O-L₃-, —S-L₃-, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-,        —O—CH₂—O—, —O—CH(L₃)-O, —S—CH(L₃)-O—, —O-L₃-, —N-L₃-, —S-L₃-,        —N(L₃)-L₅- and L₃;    -   L₄ being selected from the group consisting of nothing, C═O,        C═S,

-   -   for each L₁, L₂, and L₄, each L₃ and L₅ being independently        selected from the group consisting of nothing, H, CH₂C(═O)OL₆,        substituted and unsubstituted alkyl, substituted and        unsubstituted cycloalkyl, substituted and unsubstituted        heterocycloalkyl, substituted and unsubstituted aryl,        substituted and unsubstituted heteroaryl, substituted and        unsubstituted alkoxyl, substituted and unsubstituted alkylthio,        substituted and unsubstituted alkylamino, substituted and        unsubstituted perfluoroalkyl, and substituted and unsubstituted        alkyl halide, wherein any carbon or hydrogen may be further        independently replaced with O, S, P, NL₃, or any other        pharmaceutically acceptable groups;    -   each L₆ and each L₇ being independently selected from the group        consisting of H, OH, Cl, F, Br, I, substituted and unsubstituted        alkyl, substituted and unsubstituted cycloalkyl, and substituted        and unsubstituted heterocycloalkyl, substituted and        unsubstituted aryl, substituted and unsubstituted heteroaryl,        substituted and unsubstituted alkoxyl, substituted and        unsubstituted alkylthio, substituted and unsubstituted        alkylamino, substituted and unsubstituted perfluoroalkyl, and        substituted and unsubstituted alkyl halide, wherein any carbon        or hydrogen may be further independently replaced with O, S, N,        P(O)OL₆, CH═CH, C≡C, CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic        groups;    -   W is selected from the group consisting of H, substituted and        unsubstituted alkyl, substituted and unsubstituted cycloalkyl,        substituted and unsubstituted heterocycloalkyl, substituted and        unsubstituted alkyloxy, substituted and unsubstituted alkenyl,        substituted and unsubstituted alkynyl, substituted and        unsubstituted aryl, substituted and unsubstituted heteroaryl,        the protonatable amine group, pharmaceutically acceptable        substituted and unsubstituted amine groups, Structure Wa,        Structure W-1, Structure W-2, Structure W-3, Structure W-4,        Structure W-5, Structure W-6, Structure W-7, Structure W-8,        Structure W-9, Structure W-10, Structure W-11, Structure W-12,        Structure W-13, Structure W-14, Structure W-15, Structure W-16,        Structure W-17 and Structure W-18;    -   R₁ and R₂ are independently selected from the group consisting        of H, substituted and unsubstituted alkyl, substituted and        unsubstituted cycloalkyl, substituted and unsubstituted        heterocycloalkyl, substituted and unsubstituted alkyloxyl,        substituted and unsubstituted alkenyl, substituted and        unsubstituted alkynyl, substituted and unsubstituted aryl and        substituted and unsubstituted heteroaryl residues;    -   R₁₁-R₁₅ are independently selected from the group consisting of        nothing, H, CH₂C(═O)OR₁₁, substituted and unsubstituted alkyl,        substituted and unsubstituted cycloalkyl, substituted and        unsubstituted heterocycloalkyl, substituted and unsubstituted        alkoxyl, substituted and unsubstituted perfluoroalkyl,        substituted and unsubstituted alkyl halide, substituted and        unsubstituted alkenyl, substituted and unsubstituted alkynyl,        substituted and unsubstituted aryl, and substituted and        unsubstituted heteroaryl; and    -   any CH₂ groups may be replaced with O, S, or NH.

Linker

In certain embodiments, a linker covalently linking a functional unitand a transportational unit of an HPP comprises a bond that is capableof being cleaved after the HPP penetrates across one or more biologicalbarriers. The cleavable bond comprises, for example, a covalent bond, anether, thioether, amide, ester, thioester, carbonate, carbamate,phosphate or oxime bond.

HPP Structures

An HPP of a parent drug or a related compound of the parent drug has thefollowing Structure L-1:

including stereoisomers and pharmaceutically acceptable salts thereof;

-   -   F being a functional unit, for example, selected from the group        consisting of antihistamines, β2-adrenergic receptor agonists,        5-lipoxygenase-activating protein (FLAP) inhibitors,        5-lipoxygenase inhibitors, leukotriene receptor antagonists,        anti-inflammatory drugs, cough suppressants, decongestants and        antibiotics;    -   T being a transportational unit, for example, selected from the        group consisting of protonatable amine groups, pharmaceutically        acceptable substituted and unsubstituted primary amine groups,        pharmaceutically acceptable substituted and unsubstituted        secondary amine groups, and pharmaceutically acceptable        substituted and unsubstituted tertiary amine groups, Structure        W-1, Structure W-2, Structure W-3, Structure W-4, Structure W-5,        Structure W-6, Structure W-7, Structure W-8, Structure W-9,        Structure W-10, Structure W-11, Structure W-12, Structure W-13,        Structure W-14, Structure W-15, Structure W-16, Structure W-17        and Structure W-18 as defined supra;    -   L₁, L₂, and L₄ are defined the same as supra, in certain        embodiments, -L₁-L₄-L₂- is selected from the group consisting of        nothing, —O—, —X—, —O—X—, —N—X—, —S—X—, —X₅—, —O—X₅—, —N—X₅—,        —S—X₅—, —O—X₇—, —O—C(═O)—, —NH—C(═O)—, —C(═O)—, —C(═O)—O—,        —C(═O)—N—, and C(═O)—X—;

X being selected from the group consisting of nothing, C(═O), OC(═O),CH₂, CH, S, NH, NR₆, and O;

X₅ being selected from the group consisting of nothing, C(═O), C(═S),OC(═O), CH₂, CH, S, O and NR₅; and

X₇ is selected from the group consisting of nothing, C(═O), C(═S),OC(═O), CH₂, CH, S, O and NR₅.

An HPP of a drug that can be used to treat pulmonary conditions (e.g.asthma, lower, and upper respiratory tract infections, chronicbronchitis, chronic obstructive pulmonary disease, emphysema, cysticfibrosis, pneumonia, sarcoidosis, and pulmonary fibrosis) or a relatedcompound thereof comprises, for example, a structure selected from thegroup consisting of Structure FLAP-1, Structure FLAP-2, StructureFLAP-3, Structure FLAP-4, Structure FLAP-5, Structure FLAP-6, Structure5-LI-1-, Structure 5-LI-2, Structure 5-LI-3, Structure 5-LI-4, Structure5-LI-5, Structure 5-LI-6, Structure 5-LI-7, Structure 5-LI-8, StructureLRA-1, Structure LRA-2, Structure LRA-3, Structure LRA-4, StructureLRA-5, Structure LRA-6, Structure ARA-1, Structure ARA-2, StructureARA-3, Structure ARA-4, Structure ARA-5, Structure ARA-6, StructureARA-7, Structure ARA-8, Structure ARA-9, Structure ARA-10, StructureARA-11, Structure ARA-12, Structure ARA-13, Structure ARA-14, StructureAH-1, Structure AH-2, Structure AH-3, Structure AH-4, Structure AH-5,Structure AH-6, Structure AH-7, Structure AH-8, Structure AH-9,Structure AH-10, Structure AH-11, Structure AH-12, Structure AH-13,Structure AH-14, Structure AH-15, Structure AH-16, Structure AH-17,Structure AH-18, Structure AH-19, Structure AH-20, Structure CS-1,Structure CS-2, Structure CS-3, Structure CS-4, Structure CS-5,Structure CS-6, Structure CS-7, Structure CS-8, Structure DEC-1,Structure DEC-2, Structure DEC-3, Structure DEC-4, Structure DEC-5,Structure DEC-6, Structure NSAID-1, Structure NSAID-2, StructureNSAID-3, Structure NSAID-4, Structure NSAID-5, Structure NSAID-6,Structure NSAID-7, Structure NSAID-8, Structure NSAID-9, StructureNSAID-10, Structure NSAID-11, Structure NSAID-12, Structure NSAID-13,and Structure AB-1:

including stereoisomers and pharmaceutically acceptable salts thereof;

-   -   Aryl- is a functional unit of a HPP of an anti-inflammatory drug        or an anti-inflammatory drug-related compound, examples of Aryl-        include, without limitation, Aryl-1, Aryl-2, Aryl-3, Aryl-4,        Aryl-5, Aryl-6, Aryl-7, Aryl-8, Aryl-9, Aryl-10, Aryl-11,        Aryl-12, Aryl-13, Aryl-14, Aryl-15, Aryl-16, Aryl-17, Aryl-18,        Aryl-19, Aryl-20, Aryl-21, Aryl-22, Aryl-23, Aryl-24, Aryl-25,        Aryl-26, Aryl-27, Aryl-28, Aryl-29, Aryl-30, Aryl-31, Aryl-32,        Aryl-33, Aryl-34, Aryl-35, Aryl-36, Aryl-37, Aryl-38, Aryl-39,        Aryl-40, Aryl-41, Aryl-42, Aryl-43, Aryl-44, Aryl-45, Aryl-46,        Aryl-47, Aryl-48, Aryl-49, Aryl-50, Aryl-51, Aryl-52, Aryl-53,        Aryl-54, Aryl-55, Aryl-56, Aryl-57, Aryl-58, Aryl-59, Aryl-60,        Aryl-61, Aryl-62, Aryl-63, Aryl-64, Aryl-65, Aryl-66, Aryl-67,        Aryl-68, Aryl-69, Aryl-70, and Aryl-71:

-   -   F_(ab) is a functional unit of a HPP of an antimicrobial or        antimicrobial-related compound, examples of F_(ab) include,        without limitation, Structure FP-1, Structure FP-2, Structure        FP-3, Structure FP-4, Structure FP-5, Structure FP-6, Structure        FP-7, Structure FP-8, Structure FP-9, Structure FP-10, Structure        FP-11, Structure FP-12, Structure FP-13, Structure FP-14,        Structure FP-15, Structure FP-16, Structure FP-17, Structure        FP-18, Structure FP-19, Structure FP-20, Structure FP-21,        Structure FP-22, Structure FP-23, Structure FP-24, Structure        FP-25, Structure FP-26, Structure FP-27, Structure FP-28,        Structure FP-29, Structure FP-30, Structure FP-31, Structure        FP-32, Structure FP-33, Structure FP-34, Structure FP-35,        Structure FP-36, Structure FP-37, Structure FP-38, Structure        FP-39, Structure FP-40, Structure FP-41, Structure FP-42,        Structure FP-43, Structure FP-44, Structure FP-45, Structure        FP-46, Structure FP-47, Structure FP-48, Structure FP-49,        Structure FP-50, Structure FP-51, Structure FP-52, Structure        FP-53, Structure FP-54, Structure FP-55, Structure FP-56,        Structure FP-57, Structure FP-58, Structure FP-59, Structure        FP-60, Structure FP-61, Structure FP-62, Structure FP-63,        Structure FP-64, Structure FP-65, Structure FP-66, Structure        FP-67, Structure FP-68, Structure FP-69, Structure FP-70,        Structure FP-71, Structure FP-72, Structure FP-73, Structure        FP-74, Structure FP-75, Structure FP-76, Structure FP-77,        Structure FP-78, Structure FP-79, Structure FP-80, Structure        FP-81, Structure FP-82, Structure FP-83, Structure FP-84,        Structure FP-85, Structure FP-86, Structure FP-87, Structure        FP-88, Structure FI-1, Structure FI-2, Structure FI-3, Structure        FI-4, Structure FI-5, Structure FI-6, Structure FI-7, Structure        FI-8, Structure FI-9, Structure FI-10, Structure FI-11,        Structure FI-12, Structure FI-13, Structure FI-14, Structure        FI-15, Structure FI-16, Structure FI-17, Structure FI-18,        Structure FI-19, Structure FI-20, Structure FI-21, Structure        FI-22, Structure FI-23, Structure FI-24, Structure FI-25,        Structure FI-26, Structure FI-27, Structure FI-28, Structure        FI-29, Structure FI-30, Structure FI-31, Structure FI-32,        Structure FI-33, Structure FS-1, Structure FS-2, Structure FS-3,        Structure FS-4, Structure FS-5, Structure FS-6, Structure FS-7,        Structure FS-8, Structure FS-9, Structure FS-10, Structure        FS-11, Structure FS-12, Structure FS-13, Structure FS-14,        Structure FS-15, Structure FS-16, Structure FS-17, Structure        FS-18, Structure FS-19, Structure FS-20, Structure FT-1,        Structure FT-2, Structure FT-3, Structure FT-4, Structure FT-5,        Structure FT-6, Structure FT-7, Structure FT-8, Structure FT-9,        Structure FT-10, Structure FT-11, Structure FT-12, Structure        FT-13, Structure FT-14, Structure FT-15, Structure FT-16,        Structure FT-17, Structure FT-18, Structure FT-19, and Structure        FT-20:

-   -   HA, W, T, L₁, L₂, L₄, R₅, R₆, X₅, and X₇ being defined the same        as supra;    -   L₁ being selected from the group consisting of nothing, O, S,        —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-, —O—CH₂—O—,        —O—CH(L₃)-O, and —S—CH(L₃)-O—;        -   L₂ being selected from the group consisting of nothing, O,            S, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-, —O—CH₂—O—,            —O—CH(L₃)-O, —S—CH(L₃)-O—, —O-L₃-, —N-L₃-, —S-L₃-,            —N(L₃)-L₅- and L₃;        -   L₄ being selected from the group consisting of C═O, C═S,

-   -   -   for each L₁, L₂, and L₄, L₃ and L₅ being independently            selected from the group consisting of nothing, H,            CH₂C(═O)OL₆, substituted and unsubstituted alkyl,            substituted and unsubstituted cycloalkyl, substituted and            unsubstituted heterocycloalkyl, substituted and            unsubstituted aryl, substituted and unsubstituted            heteroaryl, substituted and unsubstituted alkoxyl,            substituted and unsubstituted alkylthio, substituted and            unsubstituted alkylamino, substituted and unsubstituted            perfluoroalkyl, and substituted and unsubstituted alkyl            halide, wherein any carbon or hydrogen may be further            independently replaced with O, S, P, NL₃, or any other            pharmaceutically acceptable groups;        -   L₆ being independently selected from the group consisting of            H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl,            substituted and unsubstituted cycloalkyl, and substituted            and unsubstituted heterocycloalkyl, substituted and            unsubstituted aryl, substituted and unsubstituted            heteroaryl, substituted and unsubstituted alkoxyl,            substituted and unsubstituted alkylthio, substituted and            unsubstituted alkylamino, substituted and unsubstituted            perfluoroalkyl, and substituted and unsubstituted alkyl            halide, wherein any carbon or hydrogen may be further            independently replaced with O, S, N, P(O)OL₆, CH═CH, C≡C,            CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic groups;        -   L₇ being independently selected from the group consisting of            H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl,            substituted and unsubstituted cycloalkyl, and substituted            and unsubstituted heterocycloalkyl, substituted and            unsubstituted aryl, substituted and unsubstituted            heteroaryl, substituted and unsubstituted alkoxyl,            substituted and unsubstituted alkylthio, substituted and            unsubstituted alkylamino, substituted and unsubstituted            perfluoroalkyl, and substituted and unsubstituted alkyl            halide, wherein any carbon or hydrogen may be further            independently replaced with O, S, N, P(O)OL₆, CH═CH, C≡C,            CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic groups; and any CH₂            groups may be replaced with O, S, or NH.            -   X₆ and X₈ being independently selected from the group                consisting of nothing, C(═O), C(═S), OC(═O), OC(═S),                CH₂, CH, S, O and NR₅;            -   Y₁, Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, Y₈, and Y₉ being                independently selected from the group consisting of H,                OH, OW, OC(═O)W, OC(═O)CH₃, CH₃, C₂H₅, C₃H₇, C₄H₉, R₆,                SO₃R₆, CH₂OR₆, CH₂OC(═O)R₆, CH₂C(═O)OR₈, OCH₃, OC₂H₅,                OR₆, CH₃SO₂, R₆SO₂, CH₃SO₃, R₆SO₃, NO₂, CN, CF₃, OCF₃,                CH₂(CH₂)_(n)NR₅R₆, CH₂(CH₂)_(n)OR₆, CH(C(═O)NH₂)NHR₆,                CH₂C(═O)NH₂, F, Br, I, Cl, CH═CHC(═O)NHCH₂C(═O)OW,                CH═CHC(═O)NHCH₂L₁-L₄-L₂-W, NR₈C(═O)R₅, SO₂NR₅R₈,                C(═O)R₅, SR₅, R₆OOCCH(NHR₇)(CH₂)_(n)C(═O)NH—,                R₆OOCCH(NHR₇)(CH₂)_(n)SC(═O)NH—, CF₃SCH₂C(═O)NH—,                CF₃CH₂C(═O)NH—, CHF₂SCH₂C(═O)NH—, CH₂FSCH₂C(═O)NH—,                NH₂C(═O)CHFS—CH₂C(═O)NH—,                R₇NHCH(C(═O)OW)CH₂SCH₂C(═O)NH—,                R₇NHCH(L₁-L₄-L₂-W)CH₂SCH₂C(═O)NH—, CNCH₂SCH₂C(═O)NH—,                CH₃(CH₂)_(n)C(═O)NH—, R₇N═CHNR₇CH₂CH₂S—,                R₇N═C(NHR₇)NHC(═O)—, R₇N═C(NHR₇)NHC(═O)CH₂,                CH₃C(Cl)═CHCH₂SCH₂C(═O)NH—, (CH₃)₂C(OR₆)—,                CNCH₂C(═O)NH—, CNCH₂CH₂S—, R₇HN═CH(NR₇)CH₂CH₂S—,                CH₂═CHCH₂SCH₂C(═O)NH—, CH₃CH(OH)—, CH₃CH(OR₈)—,                CH₃CH(Y₁)—, (CH₃)₂CH—, CH₃CH₂—,                CH₃(CH₂)_(n)CH═CH(CH₂)_(m)C(═O)NH—, substituted and                unsubstituted perfluoroalkyl, substituted and                unsubstituted alkoxyl, substituted and unsubstituted                alkylthio, substituted and unsubstituted alkylamino,                substituted and unsubstituted perfluoroalkyl,                substituted and unsubstituted alkyl halide and                substituted and unsubstituted alkylcarbonyl;            -   R₇ being independently selected from the group                consisting of H, F, Cl, Br, I,                CH₃NHC(═O)CH₂CH(NHR₈)C(═O), R₅N═C(NHR₆)NHC(═O)—,                C(═O)CH₃, C(═O)R₆, PO(OR₅)OR₆, substituted and                unsubstituted alkyl, substituted and unsubstituted                cycloalkyl, substituted and unsubstituted                heterocycloalkyl, substituted and unsubstituted                alkyloxyl, substituted and unsubstituted alkenyl,                substituted and unsubstituted alkynyl, substituted and                unsubstituted aryl, substituted and unsubstituted                heteroaryl, substituted and unsubstituted alkylcarbonyl,                substituted and unsubstituted alkylamino, L₁-L₄-L₂-W,                and C—(═O)—W;            -   R₈ being independently selected from the group                consisting of H, F, Cl, Br, I, CH₃, C₂H₅, CF₃, CH₂CH₂F,                CH₂CH₂Cl, CH₂CH₂Br, CH₂CH₂I, CH₂CHF₂, CH₂CF₃, CH₂F,                CH₂Cl, CH₂Br, CH₂I, CH₂NR₆R₇, CH(NHR₇)CH₂C(═O)NH₂, C₃H₇,                C₄H₉, C₅H₁₁, R₆, C(═O)R₆, C(═O)NH₂, CH₂C(═O)NH₂,                CH₂OC(═O)NH₂, PO(OR₅)OR₆, C(CH₃)₂C(═O)OR₆,                CH(CH₃)C(═O)OR₆, CH₂C(═O)OR₆, C(═O)—W, L₁-L₄-L₂-W, W,                substituted and unsubstituted perfluoroalkyl,                substituted and unsubstituted alkyl, substituted and                unsubstituted cycloalkyl, substituted and unsubstituted                heterocycloalkyl, substituted and unsubstituted alkoxyl,                substituted and unsubstituted alkylamino, substituted                and unsubstituted perfluoroalkyl, substituted and                unsubstituted alkyl halide and substituted and                unsubstituted alkylcarbonyl.

As used herein, the term “pharmaceutically acceptable salt” means thosesalts of compounds of the invention that are safe for application in asubject. Pharmaceutically acceptable salts include salts of acidic orbasic groups present in compounds of the invention. Pharmaceuticallyacceptable acid addition salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,11-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. For a review on pharmaceutically acceptable saltssee BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein byreference.

As used herein, unless specified otherwise, the term “alkyl” means abranched or unbranched, saturated or unsaturated, monovalent ormultivalent hydrocarbon group, including saturated alkyl groups, alkenylgroups and alkynyl groups. Examples of alkyl include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl,propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl,isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl,undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene,butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene,octylene, nonylene, decylene, undecylene and dodecylene. In certainembodiments, the hydrocarbon group contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons.

As used herein, unless specified otherwise, the term “cycloalkyl” meansan alkyl which contains at least one ring and no aromatic rings.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certainembodiments, the hydrocarbon chain contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons.

As used herein, unless specified otherwise, the term “heterocycloalkyl”means a cycloalkyl wherein at least one ring atom is a non-carbon atom.Examples of the non-carbon ring atom include, but are not limited to, S,O and N.

As used herein, unless specified otherwise, the term “alkoxyl” means analkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygenatoms. Examples of alkoxyl include, but are not limited to, —CH₂—OH,—OCH₃, —O—R_(e), —R_(e)—OH, —R_(e1)—O—R_(e2)—, wherein R_(e), R_(e1) andR_(e2) can be the same or different alkyl, cycloalkyl orheterocycloalkyl.

As used herein, unless specified otherwise, the term “alkyl halide”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore halogen atoms, wherein the halogen atoms can be the same ordifferent. The term “halogen” means fluorine, chlorine, bromine oriodine. Examples of alkyl halide include, but are not limited to,—R_(e)—F, —R_(e)—Cl, —R_(e)—Br, —R_(e)—I, —R_(e)(F)—, —R_(e)(Cl)—,—R_(e)(Br)— and —R_(e)(I)—, wherein R_(e) is an alkyl, cycloalkyl orheterocycloalkyl.

As used herein, unless specified otherwise, the term “alkylthio” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or moresulfur atoms. Examples of alkylthio include, but are not limited to,—CH₂—SH, —SCH₃, —S—R_(e), —R_(e)—SH, —R_(e1)—S—R_(e2)—, wherein R_(e),R_(e1) and R_(e2) are the same or different alkyl, cycloalkyl orheterocycloalkyl.

As used herein, unless specified otherwise, the term “alkylamino” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or morenitrogen atoms. Examples of alkylamino include, but are not limited to,—CH₂—NH, —NCH₃, —N(R_(e1))—R_(e2), —N—R_(e), —R_(e)—NH₂,—R_(e1)—N—R_(e2) and —R_(e)—N(R_(e1))—R_(e2) wherein R_(e), R_(e1) andR_(e2) are the same or different alkyl, cycloalkyl or heterocycloalkyl.

As used herein, unless specified otherwise, the term “alkylcarbonyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore carbonyl groups. Examples of alkylcarbonyl group include, but arenot limited to, aldehyde group (—R_(e)—C(O)—H), ketone group(—R_(e)—C(O)—R_(e1)), carboxylic acid group (R_(e)—C(═O)OH), ester group(—R_(e)—C(═O)O—R_(e1)), carboxamide, (—R_(e)—C(═O)O—N(R_(e1))R_(e2)),enone group (—R_(e)—C(O)—C(R_(e1))═C(R_(e2))R_(e3)), acyl halide group(—R_(e)—C(O)—X_(h)) and acid anhydride group(—R_(e)—C(O)—O—C(O)—R_(e1)), wherein R_(e), R_(e1), R_(e2) and R_(e3)are the same or different alkyl, cycloalkyl, or heterocycloalkyl; andX_(h) is a halogen.

As used herein, unless specified otherwise, the term “perfluoroalkyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore fluoro group, including, without limitation, perfluoromethyl,perfluoroethyl, perfluoropropyl.

As used herein, unless specified otherwise, the term “aryl” means achemical structure comprising one or more aromatic rings. In certainembodiments, the ring atoms are all carbon. In certain embodiments, oneor more ring atoms are non-carbon, e.g. oxygen, nitrogen, or sulfur(“heteroaryl”). Examples of aryl include, without limitation, phenyl,benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl,pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl,pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl,furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl,thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino andbenzothiazolyl.

II. Pharmaceutical Compositions Comprising HPPs

Another aspect of the invention relates to a pharmaceutical compositioncomprising at least one HPP of a parent drug that can be used to treatpulmonary conditions (e.g. asthma, lower, and upper respiratory tractinfections, chronic bronchitis, chronic obstructive pulmonary disease,emphysema, cystic fibrosis, pneumonia, sarcoidosis, and pulmonaryfibrosis) or a related compound thereof, and a pharmaceuticallyacceptable carrier.

A pharmaceutical composition may comprise more than one HPP of differentparent drugs. The different parent drugs can belong to the same ordifferent categories of drugs that are used to treat pulmonaryconditions (e.g. asthma, lower, and upper respiratory tract infections,chronic bronchitis, chronic obstructive pulmonary disease, emphysema,cystic fibrosis, pneumonia, sarcoidosis, and pulmonary fibrosis). Forexample, a pharmaceutical composition may comprise HPPs of parent drugsor related compounds thereof, the parent drugs being selected from thegroup consisting of antihistamines, β2-adrenergic receptor agonists,anti-inflammatory drugs, cough suppressants, decongestants, antibiotics,and any combinations thereof.

A pharmaceutical composition may comprise HPPs of parent drugs of thesame class of drugs that can be used to treat pulmonary conditions. Forexample, a pharmaceutical composition may comprise HPPs of more than oneantihistamines, β2-adrenergic receptor agonists, anti-inflammatorydrugs, cough suppressants, decongestants, and/or antibiotics.

A pharmaceutical composition may comprise more than one high penetrationprodrug, the first parent drug selected from the group consisting ofantihistamines, β2-adrenergic receptor agonists, anti-inflammatorydrugs, cough suppressants, decongestants, antibiotics, and anycombination thereof. The pharmaceutical composition may further compriseat least a second parent drug selected from the group consisting ofantihistamines, β2-adrenergic receptor agonists,5-lipoxygenase-activating protein (FLAP) inhibitors, 5-lipoxygenaseinhibitors, leukotriene receptor antagonists, anti-inflammatory drugs,cough suppressants, decongestants, antibiotics, and any combinationthereof. The second parent drug may also be selected from the groupconsisting of dextromethorphan, pentoxyverine, clemastine,diphenhydramine, doxylamine, desloratadine, chlorophenamine, ephedrine,and levomethamphetamin.

A pharmaceutical composition may further comprise drugs that canpenetrate biological barriers efficiently (e.g. penetrating skin at arate>0.01 mg/cm²/h). Examples of such drugs include, without limitation,dextromethorphan, pentoxyverine, clemastine, diphenhydramine,doxylamine, desloratadine, chlorophenamine, ephedrine, andlevomethamphetamine

A pharmaceutical composition may further comprise one or morecGMP-specific phosphodiesterase type 5 (PDE5) inhibitors, sildenafil,vardenafil, tadalafil, acetildenafil, avanafil, lodenafil, mirodenafil,udenafil, and derivatives and salts thereof. Examples of cGMP-specificphosphodiesterase type 5 (PDE5) inhibitors and derivatives and saltsthereof include, without limitation, Structure PDE5-I-1, StructurePDE5-I-2, Structure PDE5-I-3, Structure PDE5-I-4, Structure PDE5-I-5,Structure PDE5-I-6, Structure PDE5-I-7, and Structure PDE5-I-8 shownbelow. More specifically, Structure PDE5-I-1 is a salt of sildenafil,Structure PDE5-I-2 is a salt of vardenafil, Structure PDE5-I-3 is a saltof tadalafil, Structure PDE5-I-4 is a salt of acetildenafil, StructurePDE5-I-5 is a derivative of avanafil, Structure PDE5-I-6 is lodenafil,Structure PDE5-I-7 is a salt of mirodenafil, and Structure PDE5-I-8 is asalt of udenafil.

HA, T, L₂, and L₄ being defined the same as supra.

A pharmaceutical composition may further comprise water.

A pharmaceutical composition may further comprise an alcohols (e.g.,ethanol, glycerol, isopropanol, octanol, etc.).

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingpenicillin V and/or other antibiotics, for example, a compoundcomprising a structure of Structure AB-1; aspirin and/or otheranti-inflammatory drugs, for example, a compound comprising a structureselected from the group consisting of Structure NSAID-1, StructureNSAID-2, Structure NSAID-3, Structure NSAID-4, Structure NSAID-5,Structure NSAID-6, Structure NSAID-7, NSAID-8, Structure NSAID-9,Structure NSAID-10, Structure NSAID-11, Structure NSAID-12, andStructure NSAID-13; zileuton and/or other 5-lipoxygenase inhibitors, forexample, a compound comprising a structure selected from the groupconsisting of Structure 5-LI-1, Structure 5-LI-2, Structure 5-LI-3,Structure 5-LI-4, Structure 5-LI-5, and Structure 5-LI-6; metaproterenoland/or other leukotriene receptor antagonists, for example, a compoundcomprising a structure selected from the group consisting of StructureLRA-1, Structure LRA-2, Structure LRA-3, Structure LRA-4, StructureLRA-5, and Structure LRA-6; and fexofenadine and/or otherantihistamines, for example, a compound comprising a structure selectedfrom the group consisting of Structure AH-1, Structure AH-2, StructureAH-3, Structure AH-4, Structure AH-5, Structure AH-6, Structure AH-7,Structure AH-8, Structure AH-9, Structure AH-10, Structure AH-11,Structure AH-12, Structure AH-13, Structure AH-14, Structure AH-15,Structure AH-16, Structure AH-17, Structure AH-18, Structure AH-19, andStructure AH-20; MK-886[3-(1-(4-Chlorobenzyl)-3-t-butylthio-5-isopropylindol-2-yl)-2,2-dimethylpropanoicacid] and/or other 5-lipoxygenase-activating protein (FLAP) inhibitors,for example, a compound comprising a structure selected from the groupconsisting of Structure FLAP-1, Structure FLAP-2, Structure FLAP-3,Structure FLAP-4, Structure FLAP-5, and Structure FLAP-6; albuteroland/or other β2-adrenergic receptor agonists, for example, a compoundcomprising a structure selected from the group consisting of StructureARA-1, Structure ARA-2, Structure ARA-3, Structure ARA-4, StructureARA-5, Structure ARA-6, Structure ARA-7, Structure ARA-8, StructureARA-9, Structure ARA-10, Structure ARA-11, Structure ARA-12, StructureARA-13, and Structure ARA-14; dextromethorphan and/or other coughsuppressants, for example, a compound comprising a structure selectedfrom the group consisting of Structure CS-1, Structure CS-2, StructureCS-3, Structure CS-4, Structure CS-5, Structure CS-6, Structure CS-7,Structure CS-8; and/or ephedrine and/or other decongestants, forexample, a compound comprising a structure selected from the groupconsisting of Structure DEC-1, Structure DEC-2, Structure DEC-3,Structure DEC-4, Structure DEC-5, and Structure DEC-6; and/or sildenafiland/or other cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors,for example, a compound comprising a structure selected from the groupconsisting of Structure PDE5-I-1, Structure PDE5-I-2, StructurePDE5-I-3, Structure PDE5-I-4, Structure PDE5-I-5, Structure PDE5-I-6,Structure PDE5-I-7, and Structure PDE5-I-8.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (a HPP of penicillin V), diethylaminoethylacetylsalicylate hydrochloride (a HPP of aspirin),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (a HPP of zileuton),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (a HPP of metaproterenol), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (a HPP of fexofenadine).

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingaspirin, and zileuton.

In certain embodiments, a pharmaceutical composition comprisesdiethylaminoethyl acetylsalicylate hydrochloride, and(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingcefoxitin, aspirin, montelukast and, metaproterenol, and fexofenadine.

In certain embodiments, a pharmaceutical composition comprisesclemastine and HPPs of parent drugs or related compounds thereof, theparent drugs being cefoxitin, aspirin, montelukast, metaproterenol, andfexofenadine.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingacrivastine, cefoxitin, aspirin, montelukast, and albuterol.

In certain embodiments, a pharmaceutical composition comprises3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride (HPP of cefoxitin),diethylaminoethyl acetylsalicylate hydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride,(RS)-5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol diacetatehydrochloride (HPP of terbutaline), and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate(HPP of acrivastine).

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingcefoxitin, ibuprofen, montelukast, albuterol, and acrivastine.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingacrivastine, cefoxitin, ibuprofen, montelukast, and albuterol.

In certain embodiments, a pharmaceutical composition comprises3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, diethylaminoethyl2-(ρ-isobutylphenyl) propionate hydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride,(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride, HPP of terbutaline], and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingibuprofen, montelukast, and diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride,(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride, HPP of terbutaline], and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, wherein the parent drugs areacrivastine, cefoxitin, ibuprofen, and montelukast. In certainembodiment, the pharmaceutical composition comprises udenafil and HPPsof acrivastine, cefoxitin, ibuprofen, and montelukast.

In certain embodiments, a pharmaceutical composition comprisesdiethylaminoethyl 2-(ρ-isobutylphenyl) propionate hydrochloride,diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingdiclofenac, montelukast, pirbuterol, and acrivastine.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingacrivastine, diclofenac, montelukast, and pirbuterol.

In certain embodiments, a pharmaceutical composition comprisesdiethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate,(RS)-6-[2-(tert-butylamino)-1-acetyloxyethyl]-2-(acetyloxymethyl)-3-acetyloxypyridinehydrochloride, and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingdiflunisal, zileuton, terbutaline, and doxylamine.

In certain embodiments, a pharmaceutical composition comprisesdoxylamine and HPPs of parent drugs or related compounds thereof, theparent drugs being diflunisal, zileuton, and terbutaline.

In certain embodiments, a pharmaceutical composition comprisesdiethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, (±)-α-[(tert-butylamino)methyl]-3,5-diacetyloxybenzylalcohol acetate hydrochloride, and doxylamine.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingazlocillin, diflunisal, montelukast, and ephedrine.

In certain embodiments, a pharmaceutical composition comprises ephedrineand HPPs of parent drugs or related compounds thereof, the parent drugsbeing azlocillin, diflunisal, and montelukast.

In certain embodiments, a pharmaceutical composition comprises(2S,5R,6R)-3,3-dimethyl-7-oxo-6-{[(2R)-2-{[(2-oxoimidazolidin-1-yl)carbonyl]amino}-2-phenylacetyl]amino}-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid, diethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride,diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, and ephedrine.

In certain embodiments, a pharmaceutical composition comprises HPPs ofparent drugs or related compounds thereof, the parent drugs beingpiperacillin, aspirin, zileuton, metaproterenol, andlevomethamphetamine.

In certain embodiments, a pharmaceutical composition compriseslevomethamphetamine and HPPs of parent drugs or related compoundsthereof, the parent drugs being piperacillin, aspirin, zileuton, andmetaproterenol.

In certain embodiments, a pharmaceutical composition comprises6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride, 2-diethylaminoethyl2[(2,6-dichlorophenyl)amino]benzene acetate hydrochloride,diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride,(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride, and levomethamphetamine.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethyl esterhydrochloride, diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, sildenafil citrate (structure PDE5-I-1), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethyl esterhydrochloride, diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, sildenafil citrate, andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride.

In certain embodiments, a pharmaceutical composition comprisesdiethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate,vardenafil HCl,(R,S)α⁶-{[(1,1-dimethylethyl)amino]methyl}-3-acetyloxy-2,6-pyridinedimethanoldiacetate hydrochloride, and diphenhydramine[2-(diphenylmethoxy)-N,N-dimethylethanamine.

In certain embodiments, a pharmaceutical composition comprises3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, diethylaminoethylacetylsalicylate hydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, tadalafil, and clemastine[(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine.

In certain embodiments, a pharmaceutical composition comprises3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, diethylaminoethyl2-(ρ-isobutylphenyl) propionate hydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, udenafil, and clemastine.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethyl esterhydrochloride, diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, sildenafil citrate, andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride. In certain embodiments, apharmaceutical composition comprises3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, diethylaminoethylacetylsalicylate hydrochloride, diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, acetildenafil, and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethyl esterhydrochloride, diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, sildenafil citrate, andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride.

In certain embodiments, a pharmaceutical composition compriseslevomethamphetamine and HPPs of parent drugs or related compoundsthereof, the parent drugs being piperacillin, diclofenac, zileuton, andmetaproterenol.

In certain embodiments, a pharmaceutical composition comprises6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride, 2-diethylaminoethyl2[(2,6-dichlorophenyl)amino]benzene acetate hydrochloride,[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, acetildenafil, and isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate.

In certain embodiments, a pharmaceutical composition comprises6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethyl esterhydrochloride, diethylaminoethyl acetylsalicylate hydrochloride,(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, sildenafil citrate, andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride.

In certain embodiments, a pharmaceutical composition compriseslevomethamphetamine and HPPs of parent drugs or related compoundsthereof, the parent drugs being piperacillin, diclofenac, zileuton, andmetaproterenol.(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, and(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride.

In certain embodiments, the pharmaceutical composition comprises HPPs ofpenicillin V, aspirin, zileuton, metaproterenol, and fexofenadine.

In certain embodiments, the pharmaceutical composition comprisesclemastine and HPPs of cefoxitin, aspirin, montelukast, and terbutaline.

In certain embodiments, the pharmaceutical composition comprisesclemastine, and HPPs of cefoxitin, ibuprofen, montelukast, andterbutaline.

In certain embodiments, the pharmaceutical composition comprisesdiphenhydramine, and HPPs of diclofenac, montelukast, and pirbuterol

In certain embodiments, the pharmaceutical composition comprisesdoxylamine, and HPPs of diflunisal, zileuton, and terbutaline.

In certain embodiments, the pharmaceutical composition comprisesephedrine, and HPPs of penicillin V, diflunisal, and montelukast.

In certain embodiments, the pharmaceutical composition compriseslevomethamphetamine, and HPPs of piperacillin, diclofenac, zileuton, andmetaproterenol.

In certain embodiments, the pharmaceutical composition comprises HPPs ofpiperacillin, aspirin, zileuton, metaproterenol, and acrivastine

In certain embodiments, the pharmaceutical composition comprisessildenafil·citric acid, and HPPs of penicilin V, aspirin, zileuton, andfexofenadine.

In certain embodiments, the pharmaceutical composition comprisesvardenafil·HCl, and HPPs of penicilin V, aspirin, zileuton, andfexofenadine.

In certain embodiments, the pharmaceutical composition comprisestadalafil hydrochloride, and HPPs of cefoxitin, aspirin, montelukast,and acrivastine.

In certain embodiments, the pharmaceutical composition comprisesudenafil hydrochloride, and HPPs of cefoxitin, ibuprofen, montelukast,and acrivastine.

In certain embodiments, the pharmaceutical composition comprisessildenafil citrate, and HPPs of penicilin V, ibuprofen, zileuton, andfexofenadine.

In certain embodiments, the pharmaceutical composition comprisesvardenafil hydrochloride, and HPPs of penicilin V, ibuprofen, zileuton,and fexofenadine.

The term “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting an HPP from one location,body fluid, tissue, organ (interior or exterior), or portion of thebody, to another location, body fluid, tissue, organ, or portion of thebody.

Each carrier is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients, e.g., an HPP, of the formulationand suitable for use in contact with the tissue or organ of a biologicalsubject without excessive toxicity, irritation, allergic response,immunogenicity, or other problems or complications, commensurate with areasonable benefit/risk ratio.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations such as acetone.

The pharmaceutical compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents andthe like, for example, sodium acetate, sodium chloride, potassiumchloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueouscarrier, e.g. buffered saline and the like. In certain embodiments, thepharmaceutically acceptable carrier is a polar solvent, e.g. acetone andalcohol.

The concentration of HPP in these formulations can vary widely, and willbe selected primarily based on fluid volumes, viscosities, body weightand the like in accordance with the particular mode of administrationselected and the biological subject's needs. For example, theconcentration can be 0.0001% to 100%, 0.001% to 50%, 0.01% to 30%, 0.1%to 20%, 1% to 10% wt.

The compositions of the invention can be administered for prophylactic,therapeutic, and/or hygienic use. Such administration can be topical,mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal,subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic andother convenient routes. The pharmaceutical compositions can beadministered in a variety of unit dosage forms depending upon the methodof administration. For example, unit dosage forms suitable for oraladministration include powder, tablets, pills, capsules and lozenges andfor transdermal administration include solution, suspension and gel.

Thus, a typical pharmaceutical composition for transdermal, oral, andintravenous administrations would be about 10⁻⁸ g to about 100 g, about10⁻⁸ g to about 10⁻⁵ g, about 10⁻⁶ g to about 1 g, about 10⁻⁶ g to about100 g, about 0.001 g to about 100 g, about 0.01 g to about 10 g, orabout 0.1 g to about 1 g per subject per day. Dosages from about 0.001mg, up to about 100 g, per subject per day may be used. Actual methodsfor preparing parenterally administrable compositions will be known orapparent to those skilled in the art and are described in more detail insuch publications as Remington: The Science and Practice of Pharmacy21st ed., Lippincott Williams & Wilkins, (2005).

III. Applications of HPPs

i) Methods for Penetrating a Biological Barrier

Another aspect of the invention relates to a method of using acomposition of the invention in penetrating one or more biologicalbarriers in a biological subject. The method comprises a step ofadministering to a biological subject an HPP or a pharmaceuticalcomposition thereof. In certain embodiments, an HPP exhibits more thanabout 20 times or higher, 50 times or higher, >about 100 times orhigher, >about 200 time higher, >about 300 times or higher, >about 500times or higher, >about 1,000 times or higher penetration rate throughone or more biological barriers than its parent drug.

The term “biological barrier” as used herein refers to a biologicallayer that separates an environment into different spatial areas orcompartments, which separation is capable of modulating (e.g.restricting, limiting, enhancing or taking no action in) the passingthrough, penetrating or translocation of substance or matter from onecompartment/area to another. The different spatial areas or compartmentsas referred to herein may have the same or different chemical orbiological environment(s). The biological layer as referred hereinincludes, but is not limited to, a biological membrane, a cell layer, abiological structure, an inner surface of subjects, organisms, organs orbody cavities, an external surface of subjects, organisms, organs orbody cavities, or any combination or plurality thereof.

Examples of a biological membrane include a lipid bilayer structure,eukaryotic cell membrane, prokaryotic cell membrane, and intracellularmembrane (e.g., nucleus or organelle membrane, such as membrane orenvelope of Golgi apparatus, rough and smooth endoplasmic reticulum(ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome,nucleus, chloroplasts, plastids, peroxisomes or microbodies).

The lipid bilayer referred to herein is a double layer of lipid-classmolecules, including, but not limited to, phospholipids and cholesterol.In a particular embodiment, lipids for bilayer are amphiphilic moleculesconsisting of polar head groups and non-polar fatty acid tails. Thebilayer is composed of two layers of lipids arranged so that theirhydrocarbon tails face one another to form an oily core held together bythe hydrophobic effect, while their charged heads face the aqueoussolutions on either side of the membrane. In another particularembodiment, the lipid bilayer may contain one or more embedded proteinand/or sugar molecule(s).

Examples of a cell layer include a lining of eukaryotic cells (e.g.,epithelium, lamina propria and smooth muscle or muscularis mucosa (ingastrointestinal tract)), a lining of prokaryotic cells (e.g., surfacelayer or S-layer which refers to a two dimensional structuremonomolecular layer composed of identical proteins or glycoproteins,specifically, an S-layer refers to a part of a cell envelope commonlyfound in bacteria and archaea), a biofilm (a structured community ofmicroorganisms encapsulated within a self-developed polymeric matrix andadherent to a living or inert surface), and a plant cell layer (e.g.,empidermis). The cells may be normal cells or pathological cells (e.g.disease cells, cancer cells).

Examples of biological structures include structures sealed by tight oroccluding junctions that provide a barrier to the entry of toxins,bacteria and viruses, e.g. the blood milk barrier and the blood brainbarrier (BBB). In particular, BBB is composed of an impermeable class ofendothelium, which presents both a physical barrier through tightjunctions adjoining neighboring endothelial cells and a transportbarrier comprised of efflux transporters. The biological structure mayalso include a mixture of cells, proteins and sugars (e.g. blood clots).

Examples of the inner surface of subjects, organisms, organs or bodycavities include buccal mucosa, esophageal mucosa, gastric mucosa,intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa,uterine mucosa and endometrium (the mucosa of the uterus, inner layer ofthe wall of a pollen grain or the inner wall layer of a spore), or acombination or plurality thereof.

Examples of the external surface of subjects, organisms, organs or bodycavities include capillaries (e.g. capillaries in the heart tissue),mucous membranes that are continuous with skin (e.g. such as at thenostrils, the lips, the ears, the genital area, and the anus), outersurface of an organ (e.g. liver, lung, stomach, brain, kidney, heart,ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum,rectum stomach, colonrectum, intestine, vein, respiratory system,vascular, anorectum and pruritus ani), skin, cuticle (e.g. dead layersof epidermal cells or keratinocytes or superficial layer of overlappingcells covering the hair shaft of an animal, a multi-layered structureoutside the epidermis of many invertebrates, plant cuticles or polymerscutin and/or cutan), external layer of the wall of a pollen grain or theexternal wall layer of a spore), and a combination or plurality thereof.

In addition, a biological barrier further includes a sugar layer, aprotein layer or any other biological layer, or a combination orplurality thereof. For example, skin is a biological barrier that has aplurality of biological layers. A skin comprises an epidermis layer(outer surface), a demis layer and a subcutaneous layer. The epidermislayer contains several layers including a basal cell layer, a spinouscell layer, a granular cell layer, and a stratum corneum. The cells inthe epidermis are called keratinocytes. The stratum corneum (“hornylayer”) is the outmost layer of the epidermis, wherein cells here areflat and scale-like (“squamous”) in shape. These cells contain a lot ofkeratin and are arranged in overlapping layers that impart a tough andoilproof and waterproof character to the skin's surface.

ii) Methods for Screening a Substance for a Desired Character

Another aspect of the invention relates to a method of screening an HPPfor a desired character.

In certain embodiments, the method comprises:

-   -   1) covalently linking a test functional unit to a        transportational unit through a linker to form a test        composition (or covalently linking a functional unit to a test        transportational unit through a linker, or covalently linking a        functional unit to a transportational unit through a test        linker)    -   2) administrating the test composition to a biological subject;        and    -   3) determining whether the test composition has the desired        nature or character.

In one embodiment, a desired character may include, for example, 1) theability of a test functional unit to form a high penetration compositionor convert back to a parent drug, 2) the penetration ability and/or rateof a test composition, 3) the efficiency and/or efficacy of a testcomposition, 4) the transportational ability of a test transportationalunit, and 5) the cleavability of a test linker.

iii) Methods for Treating a Pulmonary Condition in a Biological Subject

Another aspect of the invention relates to a method of using acomposition of the invention, or a pharmaceutical composition thereof intreating a condition in a biological subject. The method comprisesadministrating the pharmaceutical composition to the biological subject.

The term “treating” as used herein means curing, alleviating,inhibiting, or preventing. The term “treat” as used herein means cure,alleviate, inhibit, or prevent. The term “treatment” as used hereinmeans cure, alleviation, inhibition or prevention.

The term “biological subject,” or “subject” as used herein means anorgan, a group of organs that work together to perform a certain task,an organism, or a group of organisms. The term “organism” as used hereinmeans an assembly of molecules that function as a more or less stablewhole and has the properties of life, such as animal, plant, fungus, ormicro-organism.

The term “animal” as used herein means a eukaryotic organismcharacterized by voluntary movement. Examples of animals include,without limitation, vertebrata (e.g. human, mammals, birds, reptiles,amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g.thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g.insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata,crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g.rotifera).

The term “plant” as used herein means organisms belonging to the kingdomPlantae. Examples of plant include, without limitation, seed plants,bryophytes, ferns and fern allies. Examples of seed plants include,without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms.Examples of bryophytes include, without limitation, liverworts,hornworts and mosses. Examples of ferns include, without limitation,ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns),marattiaceae and leptosporangiate ferns. Examples of fern alliesinclude, without limitation, lycopsida (e.g. clubmosses, spikemosses andquillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) andequisetaceae (e.g. horsetails).

The term “fungus” as used herein means a eukaryotic organism that is amember of the kingdom Fungi. Examples of fungus include, withoutlimitation, chytrids, blastocladiomycota, neocallimastigomycota,zygomycota, glomeromycota, ascomycota and basidiomycota.

The term “microorganism” as used herein means an organism that ismicroscopic (e.g. with length scale of micrometer). Examples ofmicroorganism include, without limitation, bacteria, fungi, archaea,protists and microscopic plants (e.g. green algae) and microscopicanimals (e.g. plankton, planarian and amoeba).

Some examples of the conditions the method can treat include conditionsthat can be treated by the parent drug of the HPP. For example, withoutlimitation, asthma, lower, and upper respiratory tract infections,allergic rhinitis, allergic conjunctivitis, itchiness, and runny nose.

v). Methods of Using HPPs and Pharmaceutical Compositions Thereof inTreatments of Pulmonary Conditions

Another aspect of the invention relates to a method of using HPPs orpharmaceutical compositions thereof in treating a pulmonary condition ina biological subject or subject by administrating one or more HPPs or apharmaceutical composition thereof to the biological subject or subject.

Such pulmonary conditions include, but are not limited to, asthma,lower, and upper respiratory tract infections, chronic bronchitis,chronic obstructive pulmonary disease, emphysema, cystic fibrosis,pneumonia, sarcoidosis, pulmonary fibrosis, allergic rhinitis, allergicconjunctivitis, itchiness, and runny nose.

In certain embodiments, a method of treating a pulmonary condition in asubject comprises administering a therapeutic effective amount of theone or more HPPs, or a pharmaceutical composition thereof to thesubject.

In certain embodiments, a pharmacy composition as described supracomprises a first group of HPP(s) and a pharmaceutically acceptablecarrier, wherein the parent drug(s) of the first group of HPP(s) are thefirst group of parent drug(s) comprising at least one parent drugselected from the group consisting of antihistamines, β2-adrenergicreceptor agonists, 5-lipoxygenase-activating protein (FLAP) inhibitors,5-lipoxygenase inhibitors, leukotriene receptor antagonists,anti-inflammatory drugs, cough suppressants, and decongestants. Theparent drug(s) of the first group of parent drug(s) can be the same ordifferent, and can be of the same or different type of parent drugs.Said pharmaceutical composition may further comprise a second group ofHPP(s), wherein the parent drug(s) of the second group of HPPs are thesecond group of parent drug(s), and at least one parent drug of thesecond group of parent drug(s) is selected from the group consisting ofantibiotic and anti-inflammatory drugs. The parent drug(s) of the secondgroup of parent drug(s) can be the same or different, and can be of thesame or different type of parent drugs. Said pharmaceutical compositionmay further comprise a third group of drugs selected from the groupconsisting of sildenafil, vardenafil, tadalafil, acetildenafil,avanafil, lodenafil, mirodenafil, metaproterenol, clemastine, udenafil,and salts thereof, as well as any combination thereof.

In certain embodiments, the first pharmaceutical composition comprisesthe first group, the second group, and/or the third group of HPP and apharmaceutically acceptable carrier and the first pharmaceuticalcomposition is applied first to the subject, then after the condition ofthe subject improves, a second pharmaceutical composition comprising thesecond group of HPP (e.g. HPP of aspirin) and a pharmaceuticallyacceptable carrier was administered to the subject to prevent thepulmonary condition from coming back.

The one or more HPPs or a pharmaceutical composition thereof can beadministered to a biological subject by any administration route knownin the art, including without limitation, oral, enteral, buccal, nasal,topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal,dermal, ophthalmic, pulmonary, subcutaneous, and/or parenteraladministration. The pharmaceutical compositions can be administered in avariety of unit dosage forms depending upon the method ofadministration.

A parenteral administration refers to an administration route thattypically relates to injection which includes but is not limited tointravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intra cardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, and/or intrasternal injection and/orinfusion.

The one or more HPPs or a pharmaceutical composition thereof can begiven to a subject in the form of formulations or preparations suitablefor each administration route. The formulations useful in the methods ofthe invention include one or more HPPs, one or more pharmaceuticallyacceptable carriers therefor, and optionally other therapeuticingredients. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will vary dependingupon the subject being treated and the particular mode ofadministration. The amount of an HPP which can be combined with acarrier material to produce a pharmaceutically effective dose willgenerally be that amount of an HPP which produces a therapeutic effect.Generally, out of one hundred percent, this amount will range from about0.01 percent to about ninety-nine percent of the HPP, preferably fromabout 0.1 percent to about 20 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an HPP with one or more pharmaceuticallyacceptable carriers and, optionally, one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimatelybringing into association an HPP with liquid carriers, or finely dividedsolid carriers, or both, and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of an HPP as an active ingredient. A compound mayalso be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets,pills, dragees, powders, granules and the like), the HPP is mixed withone or more pharmaceutically-acceptable carriers, such as sodium citrateor dicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate, (5) solution retarding agents,such as paraffin, (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered HPPs or HPPcompositions moistened with an inert liquid diluent. Tablets, and othersolid dosage forms, such as dragees, capsules, pills and granules, mayoptionally be scored or prepared with coatings and shells, such asenteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of an HPP therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile, other polymer matrices, liposomes and/ormicrospheres. They may be sterilized by, for example, filtration througha bacteria-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions which can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain pacifying agents and maybe of a composition that they release the HPP(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The HPP canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients.

Liquid dosage forms for oral, transdermal or topical administrationinclude pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the HPP, theliquid dosage forms may contain inert diluents commonly used in the art,such as, for example, water or other solvents, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the HPP, may contain suspending agents as,for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing one or more HPPs with oneor more suitable nonirritating excipients or carriers comprising, forexample, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the rectum or vaginal cavityand release the active agent. Formulations which are suitable forvaginal administration also include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing such carriers as areknown in the art to be appropriate.

Formulations for the topical or transdermal or epidermal or dermaladministration of an HPP composition include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive component may be mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants which may be required. The ointments, pastes,creams and gels may contain, in addition to the HPP composition,excipients, such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide, or mixturesthereof. Powders and sprays can contain, in addition to the HPPcomposition, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane. The best formulations for the topical ortransdermal administration are pure water, solution, aqueous solution,ethanol and water solution, and isopropanol and water solution.

An HPP or a pharmaceutical composition thereof can be alternativelyadministered by aerosol. This can be accomplished by preparing anaqueous aerosol, liposomal preparation or solid particles containing theHPPs. A nonaqueous (e.g., fluorocarbon propellant) suspension could beused. Sonic nebulizers can also be used. An aqueous aerosol is made byformulating an aqueous solution or suspension of the agent together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularcompound, but typically include nonionic surfactants (Tweens, Pluronics,or polyethylene glycol), innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches can also be used to deliver HPP compositions to atarget site. Such formulations can be made by dissolving or dispersingthe agent in the proper medium. Absorption enhancers can also be used toincrease the flux of the HPP compositions across the skin. The rate ofsuch flux can be controlled by either providing a rate controllingmembrane or dispersing the HPP compositions in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Formulations suitable for parenteral administration comprise an HPP incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacterostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the formulations suitable for parenteral administrationinclude water, ethanol, polyols (e.g., such as glycerol, propyleneglycol, polyethylene glycol, and the like), and suitable mixturesthereof, vegetable oils, such as olive oil, and injectable organicesters, such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

Formulations suitable for parenteral administration may also containadjuvants such as preservatives, wetting agents, emulsifying agents anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents, such as sugars,sodium chloride, and the like into the compositions. In addition,prolonged absorption of the injectable pharmaceutical form may bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices of anHPP or in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of the HPP to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly (orthoesters) andpoly (anhydrides). Depot injectable formulations are also prepared byentrapping the HPP in liposomes or microemulsions which are compatiblewith body tissue.

In certain embodiments, one or more HPPs or a pharmaceutical compositionthereof is delivered to an action site in a therapeutically effectivedose. As is known in the art of pharmacology, the precise amount of thepharmaceutically effective dose of an HPP that will yield the mosteffective results in terms of efficacy of treatment in a given patientwill depend upon, for example, the activity, the particular nature,pharmacokinetics, pharmacodynamics, and bioavailability of a particularHPP, physiological condition of the subject (including race, age, sex,weight, diet, disease type and stage, general physical condition,responsiveness to a given dosage and type of medication), the nature ofpharmaceutically acceptable carriers in a formulation, the route andfrequency of administration being used, and the severity or propensityof the condition that is to be treated. However, the above guidelinescan be used as the basis for fine-tuning the treatment, e.g.,determining the optimum dose of administration, which will require nomore than routine experimentation consisting of monitoring the subjectand adjusting the dosage. Remington: The Science and Practice ofPharmacy (Gennaro ed. 20.sup.th edition, Williams & Wilkins PA, USA)(2000).

In certain embodiments, a combination of one or more HPPs and/or otherdrug(s) is applied to the subject for the desired use (e.g. treatment,screening, etc.).

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug may be appliedseparately, or one or more of the drugs may be applied at the same timeas separate drugs (e.g. spraying two or more drugs at substantially thesame time without mixing the drugs before spraying), or one or moredrugs can be mixed together before applying to the subject, or anycombination of the above application methods. The drugs may be appliedin any order possible.

IV. Advantages

In certain embodiments, since an HPP or HPC of the invention is capableof crossing one or more biological barriers, the HPP or HPC can beadministered locally (e.g., topically or transdermally) to reach alocation where a condition occurs without the necessity of a systematicadministration (e.g., oral or parenteral administration). A localadministration and penetration of an HPP or HPC allows the HPP or HPC toreach the same level of local concentration of an agent or drug withmuch less amount or dosage of HPP or HPC in comparison to a systematicadministration of a parent agent or drug; alternatively, a higher levelof local concentration which may not be afforded in the systematicadministration, or if possible, requires significantly higher dosage ofan agent in the systematic administration. The high local concentrationof the HPP/HPC or its parent agent if being cleaved enables thetreatment of a condition more effectively or much faster than asystematically delivered parent agent and the treatment of newconditions that may not be previously possible or observed. The localadministration of the HPP or HPC may allow a biological subject toreduce potential suffering from a systemic administration, e.g., adversereactions associated with the systematic exposure to the agent,gastrointestinal/renal effects. Additionally, the local administrationmay allow the HPP or HPC to cross a plurality of biological barriers andreach systematically through, for example, general circulation and thusavoid the needs for systematic administration (e.g., injection) andobviate the pain associated with the parenteral injection.

In certain embodiments, an HPP/HPC or a pharmaceutical compositionaccording to the invention can be administered systematically (e.g.,orally, transdermally, or parenterally). The HPP/HPC or the active agent(e.g., drug or metabolite) of the HPP/HPC may enter the generalcirculation with a faster rate than the parent agent and gain fasteraccess to the action site a condition. Additionally, the HPP/HPC cancross a biological barrier (e.g., blood brain barrier and blood milkbarrier) which has not been penetrated if a parent agent is administeredalone and thus offer novel treatment of conditions that were bepreviously possible or observed.

V. Examples

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted in any way as limiting the scopeof the invention. All specific compositions, materials, and methodsdescribed below, in whole or in part, fall within the scope of theinvention. These specific compositions, materials, and methods are notintended to limit the invention, but merely to illustrate specificembodiments falling within the scope of the invention. One skilled inthe art may develop equivalent compositions, materials, and methodswithout the exercise of inventive capacity and without departing fromthe scope of the invention. It will be understood that many variationscan be made in the procedures herein described while still remainingwithin the bounds of the invention. It is the intention of the inventorsthat such variations are included within the scope of the invention.Furthermore, all references cited herein are incorporated by referencein their entireties, as if fully set forth herein.

Example 1 Preparation of an HPP from a Parent Drug

In certain embodiments, a parent compound having the following StructureF-C:

-   -   is converted to an HPP having Structure L-1:

-   -   including stereoisomers and pharmaceutically acceptable salts        thereof, wherein:    -   F, L₁, L₂, and L₄ are defined as supra;    -   T is a transportational unit of an HPP. For example, T is        selected from the group consisting of W and R₆ as defined supra.

In certain embodiments of the invention, an HPP having Structure L-1 isprepared according to organic synthesis by reacting the parent compoundsor derivatives of the parent compounds having Structure D (e.g. acidhalides, mixed anhydrides of the parent compounds, etc.):

with compounds of Structure E (Scheme 1):T-L₂-H   Structure E

-   -   wherein W_(C) is selected from the group consisting of OH,        halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy; and    -   F, L₁, L₂, L₄ and T are defined as supra.

In certain embodiments, an HPP having Structure L-1 is preparedfollowing Scheme 1 as described supra, wherein L₄ is C═O.

In certain embodiments, a parent compound having the following StructureF-N:

-   -   reacts with a compound having the following structure G:

-   -   to obtain an HPP of Structure L-1:

-   -   including stereoisomers and pharmaceutically acceptable salts        thereof, wherein:    -   F, L1, L2, and L4 are defined as supra;    -   T is a transportational unit of an HPP. For example, T is        selected from the group consisting of W and R₆ as defined supra;        and    -   M is selected from the group consisting of Na, K, or other        metal. W_(N) is selected from the group consisting of OH,        halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy.        (Scheme 2)

In certain embodiments, an HPP having a structure of Structure L-1 isprepared by organic synthesis wherein the unwanted reactive sites suchas —C(═O)OH, —NH₂, —OH, or —SH are protected before linking atransportational unit with a functional unit according to one of thesynthetic route as described supra. In certain embodiments, the obtainedprotected HPP may be further partially or completely deprotected torender a partially protected HPP or an unprotected HPP respectively.

Example 2. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethylester hydrochloride, 50 mg of diethylaminoethyl acetylsalicylatehydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (an example of a HPP of zileuton), 3 mg of(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (or metaproterenol triacetate hydrochloride, an example ofa HPP of metaproterenol), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (an example of a HPP of fexofenadine) in0.5 mL of water was applied to the skin on the thorax of a subject everymorning and evening (twice per day) until the condition was alleviated.Then 50 mg of diethylaminoethyl acetylsalicylate hydrochloride in 0.5 mlof water was applied to the skin on the thorax of the subject everymorning and evening (twice per day) to prevent the recurrence of thecondition.

Example 3. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethylester hydrochloride, 30 mg of diethylaminoethyl acetylsalicylatehydrochloride, 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (HPP of montelukast), 3 mg of(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (or metaproterenol triacetate hydrochloride, an example ofa HPP of metaproterenol), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (an example of a HPP of fexofenadine) in0.5 ml of water was applied to the skin on the thorax of a subject everymorning and evening (twice per day) until the condition was alleviated.Then 30 mg of diethylaminoethyl acetylsalicylate hydrochloride in 0.5 mlof water was applied to the skin on the thorax of the subject everymorning and evening (twice per day) to prevent the recurrence of thecondition.

Example 4. Treatment of Asthma and/or Other Pulmonary Conditions

6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride, 30 mg of diethylaminoethyl acetylsalicylatehydrochloride, 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (an example of a HPP of montelukast), 3 mg of(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (or metaproterenol triacetate hydrochloride, an example ofa HPP of metaproterenol), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (an example of a HPP of fexofenadine) in0.5 ml of water was applied to the skin on the thorax of a subject everymorning and evening (twice per day) until the condition was alleviated.Then 30 mg of diethylaminoethyl acetylsalicylate hydrochloride and 3 mgof clemastine[(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine]in 0.5 ml of water was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) to prevent the recurrence ofthe condition.

Example 5. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride (HPP of cefoxitin), 15 mgof diethylaminoethyl 2-(ρ-isobutylphenyl) propionate hydrochloride, 3 mgof diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (an example of a HPP of montelukast), 2 mg of(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride, HPP of terbutaline], and 5 mg of isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of water was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) until the condition wasalleviated. Then 30 mg of diethylaminoethyl acetylsalicylatehydrochloride and 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride in 0.5 ml of water was applied to the skin on the thoraxof a subject every morning and evening (twice per day) to prevent therecurrence of the condition.

Example 6. Treatment of Allergic Rhinitis, Allergic Conjunctivitis,Itchiness, and Runny Nose

10 mg of diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride), 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate,0.5 mg of(RS)-6-[2-(tert-butylamino)-1-acetyloxyethyl]-2-(acetyloxymethyl)-3-acetyloxypyridinehydrochloride (or pirbuterol triacetate hydrochloride, a HPP ofpirbuterol), and 10 mg of diphenhydramine[2-(diphenylmethoxy)-N,N-dimethylethanamine] in 0.5 ml of water wasapplied to the skin on the thorax of a subject every morning and evening(twice per day) until the condition was alleviated. Then 30 mg ofdiethylaminoethyl acetylsalicylate hydrochloride and 3 mg ofdiethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride in 0.5 ml of water was applied to the skin on the thoraxof a subject every morning and evening (twice per day) to prevent therecurrence of the condition.

Example 7. Treatment of Allergic Rhinitis, Allergic Conjunctivitis,Itchiness, and Runny Nose

20 mg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylatehydrochloride, 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, and 5 mg of isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of water was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) until the condition wasalleviated. Then 30 mg of diethylaminoethyl acetylsalicylatehydrochloride in 0.5 ml of water was applied to the skin on the thoraxof a subject every morning and evening (twice per day) to prevent therecurrence of the condition.

Example 8. Treatment of Lower Respiratory Tract Infection

30 mg of D-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillinicacid 2-pyrrolidinemethyl ester hydrochloride (HPP of azlocillin), 30 mgof diethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride, 3mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, and 5 mg of isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of water was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) for 2 weeks or until thecondition was alleviated. Then 30 mg of diethylaminoethylacetylsalicylate hydrochloride in 0.5 ml of water was applied to theskin on the thorax of a subject every morning and evening (twice perday) to prevent the recurrence of the condition.

Example 9. Treatment of Upper Respiratory Tract Infection

30 mg of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride (HPP of piperacillin), 10mg of 2-diethylaminoethyl 2[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride, 30 mg of diethylaminoethyl acetylsalicylatehydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, 3 mg of(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride, and 5 mg of isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of 25% ethanol was applied to the skin on the thorax of asubject every morning and evening (twice per day) for 2 weeks or untilthe condition was alleviated. Then 30 mg of diethylaminoethylacetylsalicylate hydrochloride in 0.5 ml of water was applied to theskin on the thorax of a subject every morning and evening (twice perday) to prevent the recurrence of the condition.

Example 10. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethylester hydrochloride, 30 mg of diethylaminoethyl acetylsalicylatehydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (an example of a HPP of zileuton), 15 mg of sildenafilcitrate (an example of a compound having structure PDE5-I-1, wherein HAis citric acid), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (an example of a HPP of fexofenadine) in0.5 ml of 25% ethanol was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) until the condition wasalleviated. Then 30 mg of diethylaminoethyl acetylsalicylatehydrochloride in 0.5 ml of water was applied to the skin on the thoraxof a subject every morning and evening (twice per day) to prevent therecurrence of the condition.

Example 11. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethylester hydrochloride, 30 mg of diethylaminoethyl acetylsalicylatehydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, 5 mg of vardenafil·HCl (an example of a compound havingstructure PDE5-I-2, wherein HA is HCl), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride in 0.5 ml of 25% ethanol was applied to theskin on the thorax of a subject every morning and evening (twice perday) for until the condition was alleviated. Then 30 mg ofdiethylaminoethyl acetylsalicylate hydrochloride in 0.5 ml of water wasapplied to the skin on the thorax of a subject every morning and evening(twice per day) to prevent the recurrence of the condition.

Example 12. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, 30 mg of diethylaminoethylacetylsalicylate hydrochloride, 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (an example of a HPP of montelukast), 5 mg of tadalafilHCl (an example of a compound having structure PDE5-I-3, wherein HA isHCl), and 5 mg of isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of 25% ethanol was applied to the skin on the thorax of asubject every morning and evening (twice per day) for until thecondition was alleviated. Then 30 mg of diethylaminoethylacetylsalicylate hydrochloride in 0.5 ml of water was applied to theskin on the thorax of a subject every morning and evening (twice perday) to prevent the recurrence of the condition.

Example 13. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-diethylaminoethyl ester hydrochloride, 15 mg of diethylaminoethyl2-(ρ-isobutylphenyl) propionate hydrochloride, 3 mg of diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride, 10 mg of udenafil hydrochloride (an example of a compoundhaving structure PDE5-I-8, wherein HA is HCl), and 3 mg of clemastine in1 ml of water was applied to the skin on the thorax of a subject everymorning and evening (twice per day) for 1-2 months; then 30 mg ofdiethylaminoethyl 2-(ρ-isobutylphenyl) propionate hydrochloride, 3 mg ofdiethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate,and 5 mg isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoatein 0.5 ml of 25% ethanol was applied to the skin on the thorax of asubject every morning and evening (twice per day) for until thecondition was alleviated. Then 30 mg of diethylaminoethylacetylsalicylate hydrochloride in 0.5 ml of water was applied to theskin on the thorax of a subject every morning and evening (twice perday) to prevent the recurrence of the condition.

Example 14. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-dimethylaminoethylester hydrochloride, 15 mg of diethylaminoethyl 2-(p-isobutylphenyl)propionate hydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (an example of a HPP of zileuton), 10 mg of sildenafilcitrate (an example of a compound having structure PDE5-I-1, wherein HAis citric acid), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (an example of a HPP of fexofenadine) in0.5 ml of 25% ethanol was applied to the skin on the thorax of a subjectevery morning and evening (twice per day) for until the condition wasalleviated. Then 30 mg of diethylaminoethyl acetylsalicylatehydrochloride in 0.5 ml of water was applied to the skin on the thoraxof a subject every morning and evening (twice per day) to prevent therecurrence of the condition.

Example 15. Treatment of Asthma and/or Other Pulmonary Conditions

30 mg of 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethylester hydrochloride, 15 mg of diethylaminoethyl 2-(p-isobutylphenyl)propionate hydrochloride, 30 mg of(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, 10 mg of vardenafil HCl (an example of a compound ofstructure PDE5-I-2, wherein HA is HCl), and 30 mg ofisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride in 0.5 ml of 25% ethanol was applied to theskin on the thorax of a subject every morning and evening (twice perday) for until the condition was alleviated. Then 30 mg ofdiethylaminoethyl acetylsalicylate hydrochloride in 0.5 ml of water wasapplied to the skin on the thorax of a subject every morning and evening(twice per day) to prevent the recurrence of the condition.

Example 16. Animal Test of Drug Combinations Disclosed Herein

48 female, BALB/c mice between 4 and 6 weeks of age were injectedintraperitoneally with 0.4 mL of phosphate-buffered saline containing 50μg of ovalbumin and 2.0 mg of aluminum hydroxide on day 1 and 8. Theimmunized mice were exposed to an aerosol of 2.5% ovalbumin inphosphate-buffered saline for 30 minutes/day on day 15 and 22. 12 micewere sham-immunized and challenged with phosphate-buffered saline andassigned as control group (group 1).

The 48 challenged mice were divided randomly into 5 groups: sham-controlgroup (group 1, n=6), negative control group (group 2, n=6), low dosegroup (group 3, n=12), moderate dose group (group 4, n=12) and high dosegroup (group 5, n=12). Mice in group 1 (sham-control group) and group 2(negative control group) were treated with vehicle (25% ethanol/water,the volumes administered were the same as the drug volumes of high dosegroup) once per day from day 15 to 22.

In group 3 (low dose group), each mouse was applied with a combinationof 6-phenoxyacetacetamidopenicillanic acid 3-piperidinemethyl esterhydrochloride (10 mg/kg, 2% solution in 25% ethanol/water, an HPP ofpenicillin V), dibutylaminoethyl acetylsalicylate hydrochloride (10mg/kg, 2% solution in 25% ethanol/water, an HPP of aspirin),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (an HPP of zileuton, structure AS-2) (10 mg/kg, 2%solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (or metaproterenol triacetate hydrochloride, an HPP ofmetaproterenol, structure AS-4) (1 mg/kg, 0.3% solution in 25%ethanol/water),isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,and α-dimethyl benzeneacetate hydrochloride (HPP of fexofenadine,structure AS-3) (10 mg/kg, 2% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 14 to day 22.

In group 4 (moderate dose group), each mouse was applied with acombination of 6-phenoxyacetacetamidopenicillanic acid3-piperidinemethyl ester hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water), dibutylaminoethyl acetylsalicylate hydrochloride (20mg/kg, 4% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (2 mg/kg, 0.6% solution in 25% ethanol/water), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5 (high dose group), each mouse was applied with a combinationof 6-phenoxyacetacetamidopenicillanic acid 3-piperidinemethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),dibutylaminoethyl acetylsalicylate hydrochloride (30 mg/kg, 6% solutionin 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (3 mg/kg, 0.9% solution in 25% ethanol/water), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 1 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5 6-Penicillin V 10 20 30 phenoxyacetacetamidopenicillanic acid3-piperidinemethyl ester hydrochloride dibutylaminoethylacetylsalicylate Aspirin 10 20 30 hydrochloride(RS)-N-[1-(1-benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride (RS)-5-[1-acetyloxy-2-Metaproterenol 1 2 3 (isopropylamino)ethyl]benzene- 1,3-diol diacetatehydrochloride, or metaproterenol triacetate hydrochloride isopropyl(±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30 (hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetate hydrochloride

Airway responsiveness (transpulmonary resistance (RL) and dynamiccompliance (Cdyn)) to inhaled β-methacholine was determined in mice 3hours after the last treatment with test articles and vehicle (treatmentstarted after the final challenge) at day 21. Animals were anesthetizedwith ketamine-xylazine, tracheostomized, and mechanically ventilatedwithin a plethysmograph chamber. Volume changes due to thoracicexpansion and alterations in tracheal pressure were measured in responseto challenge with saline, followed by increasing concentrations ofβ-methacholine (6.25, 12.5, 25, and 50 mg/mL). Peak values were taken asthe maximum response to the concentration of methacholine being tested,and were expressed as the percentage change relative to the salinecontrol. The results are shown in Table 1.1.

TABLE 1.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Moderatedose High dose Transpulmonary resistance  149 ± 21*  316 ± 58  187 ± 25* 156 ± 23*  148 ± 18* (percent of saline control at 25 mg/mlmethacholine) Dynamic compliance −33.7 ± 3.4* −62.5 ± 3.7 −45.2 ± 2.9*−37.1 ± 3.1* −34.8 ± 2.7* (percent of saline control at 25 mg/mlmethacholine) *P < 0.001, significant difference compared withvehicle-treated animals

Mice were euthanized with sodium pentobarbitone at day 22. The chestcavity of each animal was carefully opened, after which the trachea wasexposed and catheterized. The catheter was secured, andphosphate-buffered saline (PBS) containing 0.5% sodium citrate wasinfused in three aliquots (0.3, 0.3 and 0.4 mL, respectively) in a totalvolume of 1 mL. The bronchoalveolar lavage fluid (BALF) was recoveredand placed on ice. Total cell counts were immediately performed in aNeubauer chamber. Differential counts were obtained usingRosenfeld-stained cytospin preparations. Following centrifugation (405×gfor 5 min at 4° C.), BALF supernatants were collected and stored at −70°C. for subsequent cytokine determinations. The results are shown inTable 1.2.

TABLE 1.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in the Blood and Bronchoalveolar Lavage Fluid (BALF) NaïveVehicle Low dose Moderate dose High dose Eosinophil Numbers 0.039 ±0.008* 0.513 ± 0.105 0.180 ± 0.031  0.092 ± 0.021* 0.051 ± 0.018* inBlood (×10⁶/mL) Neutrophil Number 0.49 ± 0.16* 1.01 ± 0.12 0.65 ± 0.16*0.58 ± 0.14* 0.46 ± 0.11* in Blood (×10⁶/mL) Mononuclear cell 2.49 ±0.16  5.01 ± 0.12 2.65 ± 0.56  1.47 ± 0.28* 1.36 ± 0.21* numbers inBlood (×10⁶/mL) Eosinophil Numbers 0.29 ± 0.06* 1.81 ± 0.15 0.59 ± 0.17*0.38 ± 0.14* 0.31 ± 0.05* in BALF (×10⁶/mL) Neutrophil Number 0.35 ±0.11  0.57 ± 0.13 0.41 ± 0.15* 0.33 ± 0.18* 0.29 ± 0.11* in BALF(×10⁶/mL) Mononuclear cell 0.28 ± 0.05* 1.07 ± 0.23 0.55 ± 0.25* 0.38 ±0.20* 0.31 ± 0.12* numbers in BALF (×10⁶/mL) *P < 0.001, significantdifference compared with vehicle animals.

Mice lungs were removed, weighed and homogenized in 1.0 mL PBS,centrifuged (405×g for 5 min at 4° C.). The supernatants were collectedand stored at −70° C. for subsequent cytokine determinations. Cytokinelevels were determined per mg of tissue. Commercially availableenzyme-linked immunosorbent assay antibodies were used to measure IL-5in lung homogenates. Sensitivities were >10 pg/mL. The results are shownin Table 1.3.

TABLE 1.3 IL-5 in lung homogenates of animals Group No. 1 2 3 4 5 Drugadministered Naïve Vehicle Low dose Moderate dose High dose IL-5(pg/mgof 0.39 ± 0.12* 1.11 ± 0.09 0.59 ± 0.10* 0.43 ± 0.08* 0.37 ± 0.08*tissue) *P < 0.001, significant difference compared with vehicleanimals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 17. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Doses and HPPs of the same parentdrug but optionally different transportational units were applied assummarized in Table 2.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 2 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5 6-Penicillin V 10 20 30 phenoxyacetacetamidopenicillanic acid2-(diethylamino)-1- methylethyl ester hydrochloride 1-piperidineethylacetylsalicylate Aspirin 10 20 30 hydrochloride(RS)-N-[1-(1-benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride (RS)-5-[1-acetyloxy-2-Metaproterenol 1 2 3 (isopropylamino)ethyl]benzene- 1,3-diol diacetatehydrochloride isopropyl (±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30(hydroxydiphenylmethyl)-1- piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride

More specifically, in group 3, each mouse was applied with a combinationof 6-phenoxyacetacetamidopenicillanic acid2-(diethylamino)-1-methylethyl ester hydrochloride (10 mg/kg, 2%solution in 25% ethanol/water), 1-piperidineethyl acetylsalicylatehydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (1 mg/kg, 0.3% solution in 25% ethanol/water), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (HPP of fexofenadine, structure AS-3) (10mg/kg, 2% solution in 25% ethanol/water) to the shaved skin on the neckonce per day from day 14 to day 22.

In group 4 (moderate dose group), each mouse was applied with acombination of 6-phenoxyacetacetamidopenicillanic acid2-diethylaminoethyl ester hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water), 1-piperidineethyl acetylsalicylate hydrochloride (20mg/kg, 4% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (2 mg/kg, 0.6% solution in 25% ethanol/water), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5 (high dose group), each mouse was applied with a combinationof 6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),1-piperidineethyl acetylsalicylate hydrochloride (30 mg/kg, 6% solutionin 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (3 mg/kg, 0.9% solution in 25% ethanol/water), andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 2.1.

TABLE 2.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  151 ± 23*  311 ± 68  191 ± 21*  151± 20*  142 ± 17* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −32.1 ± 3.0* −63.5 ± 3.1 −47.2 ± 2.3* −39.0 ± 2.8*−34.1 ± 2.9* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 2.2.

TABLE 2.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.037 ± 0.010* 0.529 ± 0.132 0.182 ± 0.028 0.090 ± 0.014* 0.047± 0.015* in Blood (×10⁶/mL) Neutrophil Number 0.51 ± 0.13* 1.12 ± 0.16 0.67 ± 0.18* 0.62 ± 0.11* 0.43 ± 0.15* in Blood (×10⁶/mL) Mononuclearcell 2.21 ± 0.16  5.09 ± 0.17 2.69 ± 0.47 1.57 ± 0.22* 1.32 ± 0.25*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.31 ± 0.05* 1.87 ± 0.16 0.57 ± 0.21* 0.41 ± 0.12* 0.34 ± 0.08* in BALF (×10⁶/mL) NeutrophilNumber 0.32 ± 0.13* 0.59 ± 0.16  0.40 ± 0.13* 0.35 ± 0.14* 0.28 ± 0.13*in BALF (×10⁶/mL) Mononuclear cell 0.29 ± 0.07* 1.10 ± 0.21 0.59 ± 0.270.42 ± 0.18* 0.34 ± 0.10* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 2.3.

TABLE 2.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.38 ± 0.15* 1.09 ± 0.12 0.62 ±0.14* 0.45 ± 0.11* 0.39 ± 0.07* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 18. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), 3-piperidinemethyl acetylsalicylate hydrochloride(10 mg/kg, 2% solution in 25% ethanol/water), diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (1 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (0.6 mg/kg, 0.2% solution in 25% ethanol/water), andclemastine[(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine(1 mg/kg, 0.3% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 14 to day 22.

in group 4, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), 3-piperidinemethyl acetylsalicylate hydrochloride(20 mg/kg, 4% solution in 25% ethanol/water), diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (2 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (1.2 mg/kg, 0.4% solution in 25% ethanol/water), andclemastine[(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine(2 mg/kg, 0.6% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), 3-piperidinemethyl acetylsalicylate hydrochloride(30 mg/kg, 6% solution in 25% ethanol/water), diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (3 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (1.8 mg/kg, 0.6% solution in 25% ethanol/water), andclemastine[(2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine(3 mg/kg, 0.9% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 3.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 3 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 53-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8- Cefoxitin 10 20 30oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 4- piperidinemethyl esterhydrochloride 1-piperidineethyl acetylsalicylate hydrochloride Aspirin10 20 30 2-(diethylamino)ethyl [R-(E)]-1-[[[1-[3-[2-(7- Montelukast 1 23 chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1- hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopro- paneacetatehydrochloride (RS)-5-[2-(tert-butylamino)-1- Terbutaline 0.6 1.2 1.8acetyloxyethyl]benzene-1,3-diol diacetate hydrochloride Clemastine N/A 12 3

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in table 3.1.

TABLE 3.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  159 ± 21*  322 ± 60  194 ± 18*  157± 18*  141 ± 19* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −34.5 ± 3.1* −64.1 ± 3.9 −46.9 ± 2.1* −39.8 ± 2.6*−35.3 ± 2.6* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 3.2.

TABLE 3.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.031 ± 0.011* 0.572 ± 0.121 0.192 ± 0.023 0.095 ± 0.021* 0.047± 0.015* in Blood (×10⁶/mL) Neutrophil Number 0.57 ± 0.16* 1.17 ± 0.15 0.69 ± 0.21* 0.57 ± 0.14* 0.53 ± 0.12* in Blood (×10⁶/mL) Mononuclearcell 2.09 ± 0.19  5.17 ± 0.21 2.73 ± 0.36 1.79 ± 0.23* 1.65 ± 0.20*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.30 ± 0.07* 1.80 ± 0.15 0.59 ± 0.18* 0.45 ± 0.10* 0.37 ± 0.10* in BALF (×10⁶/mL) NeutrophilNumber 0.36 ± 0.11* 0.61 ± 0.09 0.45 ± 0.21 0.39 ± 0.10* 0.34 ± 0.10* inBALF (×10⁶/mL) Mononuclear cell 0.33 ± 0.09* 1.15 ± 0.23 0.61 ± 0.290.47 ± 0.21* 0.32 ± 0.15* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 3.3.

TABLE 3.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.33 ± 0.11* 1.13 ± 0.15 0.58 ±0.17* 0.41 ± 0.16* 0.36 ± 0.09* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 19. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionatehydrochloride (5 mg/kg, 1% solution in 25% ethanol/water),2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride (1 mg/kg, 0.3% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (0.6 mg/kg, 0.2% solution in 25% ethanol/water), andclemastine (1 mg/kg, 0.3% solution in 25% ethanol/water) to the shavedskin on the neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionatehydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride (2 mg/kg, 0.6% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (1.2 mg/kg, 0.4% solution in 25% ethanol/water), andclemastine (2 mg/kg, 0.6% solution in 25% ethanol/water) to the shavedskin on the neck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 4-piperidinemethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), 3-piperidinemethyl 2-(ρ-isobutylphenyl) propionatehydrochloride (15 mg/kg, 3% solution in 25% ethanol/water),2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride (3 mg/kg, 0.9% solution in 25% ethanol/water),(RS)-5-[2-(tert-butylamino)-1-acetyloxyethyl]benzene-1,3-diol diacetatehydrochloride (1.8 mg/kg, 0.6% solution in 25% ethanol/water), andclemastine (3 mg/kg, 0.9% solution in 25% ethanol/water) to the shavedskin on the neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 4.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 4 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 53-[[(Aminocarbonyl)oxy]methyl]-7-methoxy-8- Cefoxitin 10 20 30oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 4-piperidinemethyl esterhydrochloride 3-Piperidinemethyl 2-(ρ-isobutylphenyl) Ibuprofen 5 10 15propionate hydrochloride 2-Pyrrolidinemethyl 2-[1-[[(1R)-1-[3-[2-(7-Montelukast 1 2 3 chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2- yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride (RS)-5-[2-(Tert-butylamino)-1- Terbutaline 0.6 1.2 1.8acetyloxyethyl]benzene-1,3-diol diacetate hydrochloride Clemastine N/A 12 3

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 4.1.

TABLE 4.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  166 ± 20*  326 ± 52  196 ± 13*  157± 19*  149 ± 12* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −34.7 ± 3.3* −63.1 ± 2.9 −47.3 ± 2.3* −41.2 ± 2.3*−34.3 ± 2.7* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 4.2.

TABLE 4.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.033 ± 0.014* 0.590 ± 0.131 0.197 ± 0.023 0.097 ± 0.022* 0.041± 0.013* in Blood (×10⁶/mL) Neutrophil Number 0.58 ± 0.14* 1.15 ± 0.17 0.71 ± 0.18* 0.58 ± 0.15* 0.51 ± 0.14* in Blood (×10⁶/mL) Mononuclearcell 2.25 ± 0.17  5.17 ± 0.23 2.75 ± 0.38 1.82 ± 0.21* 1.60 ± 0.23*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.31 ± 0.08* 1.80 ± 0.14 0.56 ± 0.16* 0.47 ± 0.12* 0.39 ± 0.11* in BALF (×10⁶/mL) NeutrophilNumber 0.38 ± 0.10* 0.62 ± 0.08 0.48 ± 0.28 0.41 ± 0.09* 0.38 ± 0.12* inBALF (×10⁶/mL) Mononuclear cell 0.31 ± 0.06* 1.09 ± 0.22 0.67 ± 0.320.45 ± 0.20* 0.33 ± 0.12* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 4.3.

TABLE 4.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.31 ± 0.13* 1.15 ± 0.19 0.59 ±0.18* 0.43 ± 0.15* 0.37 ± 0.08* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 20. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of2-pyrrolidinemethyl 2-[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride (3 mg/kg, 1% solution in 25% ethanol/water),diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate(HPP of montelukast, 1 mg/kg, 0.3% solution in 25% ethanol/water),(R,S)α⁶-{[(1,1-dimethylethyl)amino]methyl}-3-acetyloxy-2,6-pyridinedimethanoldiacetate hydrochloride (0.2 mg/kg, 0.1% solution in 25% ethanol/water)and diphenhydramine (3 mg/kg, 1% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of2-pyrrolidinemethyl 2-[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride (6 mg/kg, 2% solution in 25% ethanol/water),diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate(2 mg/kg, 0.6% solution in 25% ethanol/water),(R,S)α⁶-{[(1,1-dimethylethyl)amino]methyl}-3-acetyloxy-2,6-pyridinedimethanoldiacetate hydrochloride (0.4 mg/kg, 0.2% solution in 25% ethanol/water)and diphenhydramine (6 mg/kg, 2% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of2-pyrrolidinemethyl 2-[(2,6-dichlorophenyl)amino]benzene acetatehydrochloride (9 mg/kg, 3% solution in 25% ethanol/water),diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate(3 mg/kg, 0.9% solution in 25% ethanol/water),(R,S)α⁶-{[(1,1-dimethylethyl)amino]methyl}-3-acetyloxy-2,6-pyridinedimethanoldiacetate hydrochloride (0.5 mg/kg, 0.3% solution in 25% ethanol/water)and diphenhydramine (9 mg/kg, 3% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 5.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 5 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 52-pyrrolidinemethyl 2-[(2,6- Diclofenac 3 6 9dichlorophenyl)amino]benzene acetate hydrochloride diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7- Montelukast 1 2 3chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2- hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate(R,S)α⁶-{[(1,1-dimethylethyl) amino]methyl}- Pirbuterol 0.2 0.4 0.53-acetyloxy-2,6-pyridinedimethanol diacetate hydrochlorideDiphenhydramine N/A 3 6 9

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 5.1.

TABLE 5.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  161 ± 18*  331 ± 46 211 ± 19  168 ±18*  157 ± 15* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −34.2 ± 3.0* −62.1 ± 2.7 −47.6 ± 2.1* −45.2 ± 2.0*−37.3 ± 2.1* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results were shown in Table 5.2.

TABLE 5.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.039 ± 0.015* 0.599 ± 0.115 0.190 ± 0.025 0.098 ± 0.021* 0.045± 0.015* in Blood (×10⁶/mL) Neutrophil Number 0.57 ± 0.15* 1.18 ± 0.22 0.76 ± 0.17* 0.62 ± 0.14* 0.57 ± 0.18* in Blood (×10⁶/mL) Mononuclearcell 2.01 ± 0.18  5.07 ± 0.26 2.78 ± 0.42 1.86 ± 0.20* 1.69 ± 0.26*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.30 ± 0.11* 1.82 ± 0.17 0.58 ± 0.19* 0.49 ± 0.17* 0.42 ± 0.15* in BALF (×10⁶/mL) NeutrophilNumber 0.36 ± 0.13* 0.69 ± 0.12 0.51 ± 0.29 0.44 ± 0.07* 0.39 ± 0.13* inBALF (×10⁶/mL) Mononuclear cell 0.30 ± 0.08* 1.07 ± 0.25 0.69 ± 0.310.48 ± 0.22* 0.41 ± 0.14* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 5.3.

TABLE 5.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.31 ± 0.13* 1.15 ± 0.19 0.59 ±0.18* 0.43 ± 0.15* 0.37 ± 0.08* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 21. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination ofdiethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride (7mg/kg, 1.5% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, (10 mg/kg, 2% solution in 25% ethanol/water),(±)-α-[(tert-butylamino)methyl]-3,5-diacetyloxybenzyl alcohol acetatehydrochloride (0.07 mg/kg, 0.05% solution in 25% ethanol/water), anddoxylamine[(RS)—N,N-dimethyl-2-(1-phenyl-1-pyridine-2-yl-ethoxy)-ethanamine](3mg/kg, 0.6% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination ofdiethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride (14mg/kg, 3% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, (20 mg/kg, 4% solution in 25% ethanol/water),(±)-α-[(tert-butylamino)methyl]-3,5-diacetyloxybenzyl alcohol acetatehydrochloride (0.14 mg/kg, 0.1% solution in 25% ethanol/water), anddoxylamine (6 mg/kg, 1.2% solution in 25% ethanol/water) to the shavedskin on the neck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination ofdiethylaminoethyl 5-(2,4-difluorophenyl)salicylate hydrochloride (20mg/kg, 4.5% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride, (30 mg/kg, 6% solution in 25% ethanol/water),(±)-α-[(tert-butylamino)methyl]-3,5-diacetyloxybenzyl alcohol acetatehydrochloride (0.2 mg/kg, 0.15% solution in 25% ethanol/water), anddoxylamine (9 mg/kg, 2% solution in 25% ethanol/water) to the shavedskin on the neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 6.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 6 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5Diethylaminoethyl 5-(2,4- Diflunisal 7 14 20 difluorophenyl)salicylatehydrochloride (RS)-N-[1-(1-Benzothien-2- Zileuton 10 20 30yl)ethyl]-N-(2- diethylaminoacetyloxy)urea hydrochloride (±)-Terbutaline 0.04 0.14 0.2 α-[(Tert-butylamino)methyl]-3,5-diacetyloxybenzyl alcohol acetate hydrochloride Doxylamine N/A 3 6 9

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 6.1.

TABLE 6.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  149 ± 20*  320 ± 57  198 ± 25  162± 17*  155 ± 22* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −34.1 ± 2.8* −64.5 ± 3.2 −48.9 ± 3.5 −41.8 ± 2.0*−37.9 ± 3.6* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results were shown in Table 6.2.

TABLE 6.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.041 ± 0.010* 0.592 ± 0.134 0.232 ± 0.028 0.097 ± 0.025* 0.056± 0.019* in Blood (×10⁶/mL) Neutrophil Number 0.58 ± 0.18* 1.19 ± 0.180.75 ± 0.30 0.56 ± 0.15* 0.54 ± 0.17* in Blood (×10⁶/mL) Mononuclearcell 2.01 ± 0.17* 5.19 ± 0.25 2.69 ± 0.39 1.84 ± 0.20* 1.61 ± 0.25*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.33 ± 0.08* 1.83 ± 0.17 0.58 ± 0.20* 0.49 ± 0.12* 0.39 ± 0.15* in BALF (×10⁶/mL) NeutrophilNumber 0.35 ± 0.14* 0.62 ± 0.12 0.47 ± 0.26 0.42 ± 0.12* 0.38 ± 0.15* inBALF (×10⁶/mL) Mononuclear cell 0.32 ± 0.08* 1.17 ± 0.27 0.72 ± 0.330.58 ± 0.15* 0.37 ± 0.18* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 6.3.

TABLE 6.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.37 ± 0.13* 1.16 ± 0.25 0.68 ±0.19* 0.48 ± 0.22* 0.41 ± 0.11* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test Combinations have stronganti-inflammatory and anti-asthma activities.

Example 22. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination ofD-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin2-pyrrolidinemethyl ester hydrochloride (10 mg/kg, 2% solution in 25%ethanol/water), diethylaminoethyl 5-(2,4-difluorophenyl)salicylatehydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (1 mg/kg, 0.3% solution in 25% ethanol/water), andephedrine (3 mg/kg, 1% solution in 25% ethanol/water) to the shaved skinon the neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination ofD-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin2-pyrrolidinemethyl ester hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water), diethylaminoethyl 5-(2,4-difluorophenyl)salicylatehydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (2 mg/kg, 0.6% solution in 25% ethanol/water), andephedrine (6 mg/kg, 2% solution in 25% ethanol/water) to the shaved skinon the neck of mice once per day from day 15 to 22.

In group 5, each mouse was applied with a combination ofD-α-[(imidazolidin-2-on-1-yl)carbonylamino]benzylpenicillin2-pyrrolidinemethyl ester hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water), diethylaminoethyl 5-(2,4-difluorophenyl)salicylatehydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (3 mg/kg, 0.9% solution in 25% ethanol/water), andephedrine (9 mg/kg, 3% solution in 25% ethanol/water) to the shaved skinon the neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 7.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 7 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5D-α-[(Imidazolidin-2-on-1- Penicillin 10 20 30yl)carbonylamino]benzylpenicillin 2- V pyrrolidinemethyl esterhydrochloride Diethylaminoethyl 5-(2,4- Diflunisal 10 20 30difluorophenyl)salicylate hydrochloride Diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro- Montelukast 1 2 32-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopro- paneacetatehydrochloride Ephedrine N/A 3 6 9

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 7.1.

TABLE 7.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  149 ± 21*  307 ± 65  195 ± 17*  162± 23*  152 ± 18* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −31.1 ± 3.1* −62.5 ± 3.5 −48.2 ± 3.1* −43.0 ± 2.5*−34.9 ± 3.0* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 7.2.

TABLE 7.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.041 ± 0.011* 0.592 ± 0.132 0.189 ± 0.048 0.099 ± 0.017* 0.046± 0.018* in Blood (×10⁶/mL) Neutrophil Number 0.50 ± 0.15* 1.17 ± 0.18 0.72 ± 0.15* 0.65 ± 0.13* 0.49 ± 0.19* in Blood (×10⁶/mL) Mononuclearcell 2.80 ± 0.16* 5.21 ± 0.18 2.61 ± 0.48 1.56 ± 0.25* 1.30 ± 0.29*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.34 ± 0.06* 1.86 ± 0.18 0.69 ± 0.18* 0.48 ± 0.15* 0.39 ± 0.18* in BALF (×10⁶/mL) NeutrophilNumber 0.30 ± 0.13* 0.58 ± 0.17  0.42 ± 0.11* 0.38 ± 0.16* 0.36 ± 0.15*in BALF (×10⁶/mL) Mononuclear cell 0.27 ± 0.11* 1.11 ± 0.23 0.67 ± 0.330.48 ± 0.17* 0.38 ± 0.15* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 7.3.

TABLE 7.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.35 ± 0.13* 1.12 ± 0.15 0.65 ±0.12* 0.48 ± 0.13* 0.38 ± 0.12* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 23. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), 2-diethylaminoethyl2[(2,6-dichlorophenyl)amino]benzene acetate hydrochloride (3 mg/kg, 0.6%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (HPP of zileuton, 10 mg/kg, 2% solution in 25%ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (1 mg/kg, 0.2% solution in 25% ethanol/water), andlevomethamphetamine (3 mg/kg, 0.6% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), 2-diethylaminoethyl2[(2,6-dichlorophenyl)amino]benzene acetate hydrochloride (6 mg/kg, 1.2%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-ethylaminoacetyloxyl)ureahydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (2 mg/kg, 0.4% solution in 25% ethanol/water), andlevomethamphetamine (6 mg/kg, 1.2% solution in 25% ethanol/water) to theshaved skin on the neck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-diethylaminoethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), 2-diethylaminoethyl2[(2,6-dichlorophenyl)amino]benzene acetate hydrochloride (9 mg/kg, 2%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (3 mg/kg, 0.6% solution in 25% ethanol/water), andlevomethamphetamine (9 mg/kg, 1.8% solution in 25% ethanol/water) (6mg/kg, 2% solution in 25% ethanol/water) to the shaved skin on the neckonce per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 8.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 8 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 56-D(−)-α-(4-ethyl-2,3-dioxo-1- Piperacillin 10 20 30piperazinylcarbonylamino)-α- phenylacetamidopenicillinic acid2-diethylaminoethyl ester hydrochloride 2-diethylaminoethyl 2[(2,6-Diclofenac 3 6 9 dichlorophenyl)amino]benzene acetate hydrochloride(RS)-N-[1-(1-benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride (RS)-5-[1-acetyloxy-2-Metaproterenol 1 2 3 (isopropylamino)ethyl]benzene- 1,3-diol diacetatehydrochloride Levomethamphetamine N/A 3 6 9

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 8.1.

TABLE 8.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  153 ± 21*  313 ± 61  196 ± 17*  163± 18*  152 ± 19* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −33.1 ± 2.8* −63.1 ± 3.2 −48.2 ± 2.5* −39.5 ± 2.9*−36.1 ± 2.8* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 8.2.

TABLE 8.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.038 ± 0.012* 0.519 ± 0.102 0.189 ± 0.033 0.096 ± 0.017* 0.049± 0.019* in Blood (×10⁶/mL) Neutrophil Number 0.50 ± 0.14* 1.15 ± 0.19 0.69 ± 0.21* 0.61 ± 0.17* 0.55 ± 0.18* in Blood (×10⁶/mL) Mononuclearcell 2.27 ± 0.18* 5.12 ± 0.29 2.79 ± 0.53 1.68 ± 0.21* 1.55 ± 0.27*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.30 ± 0.07* 1.82 ± 0.18 0.65 ± 0.24* 0.52 ± 0.17* 0.41 ± 0.16* in BALF (×10⁶/mL) NeutrophilNumber 0.35 ± 0.16* 0.61 ± 0.21  0.42 ± 0.15* 0.39 ± 0.16* 0.36 ± 0.17*in BALF (×10⁶/mL) Mononuclear cell 0.31 ± 0.10* 1.11 ± 0.16 0.63 ± 0.290.47 ± 0.15* 0.42 ± 0.11* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 8.3.

TABLE 8.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.37 ± 0.14* 1.14 ± 0.19 0.65 ±0.15* 0.53 ± 0.14* 0.41 ± 0.11* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 23. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-(diethylamino)ethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), diethylaminoethyl acetylsalicylate hydrochloride (10mg/kg, 2% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (HPP of zileuton, 10 mg/kg, 2% solution in 25%ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (1 mg/kg, 0.2% solution in 25% ethanol/water) and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(1.5 mg/kg, 0.1% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-(diethylamino)ethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), diethylaminoethyl acetylsalicylate hydrochloride (20mg/kg, 4% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (2 mg/kg, 0.4% solution in 25% ethanol/water) and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(3 mg/kg, 0.2% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of6-D(−)-α-(4-ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-α-phenylacetamidopenicillinicacid 2-(diethylamino)ethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), diethylaminoethyl acetylsalicylate hydrochloride (30mg/kg, 6% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),(RS)-5-[1-acetyloxy-2-(isopropylamino)ethyl]benzene-1,3-diol diacetatehydrochloride (3 mg/kg, 0.6% solution in 25% ethanol/water) and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(4.5 mg/kg, 0.3% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 9.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 9 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug Dose DoseDose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 56-D(−)-α-(4-ethyl-2,3-dioxo-1- Piperacillin 10 20 30piperazinylcarbonylamino)-α- phenylacetamidopenicillinic acid2-(diethylamino)ethyl ester hydrochloride diethylaminoethylacetylsalicylate Aspirin 10 20 30 hydrochloride(RS)-N-[1-(1-benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride (RS)-5-[1-acetyloxy-2-Metaproterenol 1 2 3 (isopropylamino)ethyl]benzene- 1,3-diol diacetatehydrochloride (isopropyl (E)-3-{6-[(E)-1-(4- Acrivastine 1.5 3 4.5methylphenyl)-3-pyrrolidine-1-yl- prop-1-enyl]pyridin-2-yl}prop-2-enoate)

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 9.1.

TABLE 9.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  151 ± 23*  311 ± 68  191 ± 21*  151± 20*  142 ± 17* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −32.1 ± 3.0* −63.5 ± 3.1 −47.2 ± 2.3* −39.0 ± 2.8*−34.1 ± 2.9* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 9.2.

TABLE 9.2 Eosinophil numbers, neutrophil number and mononuclearcellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.037 ± 0.010* 0.529 ± 0.132 0.182 ± 0.028 0.090 ± 0.014* 0.047± 0.015* in Blood (×10⁶/mL) Neutrophil Number 0.51 ± 0.13* 1.12 ± 0.16 0.67 ± 0.18* 0.62 ± 0.11* 0.43 ± 0.15* in Blood (×10⁶/mL) Mononuclearcell 2.21 ± 0.16  5.09 ± 0.17 2.69 ± 0.47 1.57 ± 0.22* 1.32 ± 0.25*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.31 ± 0.05* 1.87 ± 0.16 0.57 ± 0.21* 0.41 ± 0.12* 0.34 ± 0.08* in BALF (×10⁶/mL) NeutrophilNumber 0.32 ± 0.13* 0.59 ± 0.16  0.40 ± 0.13* 0.35 ± 0.14* 0.28 ± 0.13*in BALF (×10⁶/mL) Mononuclear cell 0.29 ± 0.07* 1.10 ± 0.21 0.59 ± 0.270.42 ± 0.18* 0.34 ± 0.10* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table 9.3.

TABLE 9.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.38 ± 0.15* 1.09 ± 0.12 0.62 ±0.14* 0.45 ± 0.11* 0.39 ± 0.07* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 25. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (10 mg/kg, 2%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (HPP of zileuton, 10 mg/kg, 2% solution in 25%ethanol/water), sildenafil·citric acid (5 mg/kg, 2% in 25%ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (10 mg/kg, 2% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 14to day 22.

In group 4, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (20 mg/kg, 4%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),sildenafil·citric acid (10 mg/kg, 4% in 25% ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (30 mg/kg, 6%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),sildenafil·citric acid (15 mg/kg, 6% in 25% ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 10.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 10 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug DoseDose Dose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5 6-Penicilin V 10 20 30 phenoxyacetacetamidopenicillanic acid2-(diethylamino)ethyl ester hydrochloride 2-(diethylamino)ethyl Aspirin10 20 30 acetylsalicylate hydrochloride (RS)-N-[1-(1-benzothien-2-Zileuton 10 20 30 yl)ethyl]-N-(2- diethylaminoacetyloxy)ureahydrochloride sildenafil•citric acid N/A 5 10 15 (isopropyl(±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30 (hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetate hydrochloride

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 10.1.

TABLE 10.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  149 ± 24*  317 ± 61  193 ± 20*  157± 21*  143 ± 18* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −33.1 ± 3.1* −63.9 ± 3.2 −47.9 ± 2.1* −39.9 ± 3.1*−35.1 ± 2.6* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 10.2.

TABLE 10.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.035 ± 0.011* 0.539 ± 0.135 0.199 ± 0.025 0.098 ± 0.015* 0.052± 0.018* in Blood (×10⁶/mL) Neutrophil Number 0.52 ± 0.15* 1.15 ± 0.18 0.69 ± 0.21* 0.61 ± 0.15* 0.48 ± 0.18* in Blood (×10⁶/mL) Mononuclearcell 2.27 ± 0.17  5.12 ± 0.19 2.77 ± 0.48 1.54 ± 0.23* 1.36 ± 0.27*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.35 ± 0.05* 1.89 ± 0.17 0.63 ± 0.22* 0.48 ± 0.15* 0.36 ± 0.11* in BALF (×10⁶/mL) NeutrophilNumber 0.31 ± 0.15* 0.61 ± 0.18  0.42 ± 0.15* 0.38 ± 0.16* 0.33 ± 0.15*in BALF (×10⁶/mL) Mononuclear cell 0.31 ± 0.08* 1.12 ± 0.23 0.61 ± 0.290.43 ± 0.19* 0.35 ± 0.12* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table10.3.

TABLE 10.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.39 ± 0.15* 1.10 ± 0.13 0.65 ±0.15* 0.47 ± 0.12* 0.42 ± 0.09* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 26. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (10 mg/kg, 2%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),vardenafil·HCl (1.5 mg/kg, 0.5% in 25% ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (10 mg/kg, 2% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 14to day 22.

In group 4, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (20 mg/kg, 4%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),vardenafil·HCl (3 mg/kg, 1% in 25% ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-(diethylamino)ethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),2-(diethylamino)ethyl acetylsalicylate hydrochloride (30 mg/kg, 6%solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),vardenafil·HCl (4.5 mg/kg, 1.5% in 25% ethanol/water), and(isopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 11.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 11 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug DoseDose Dose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 5 6-Penicilin V 10 20 30 Phenoxyacetacetamidopenicillanic acid2-(diethylamino)ethyl ester hydrochloride 2-(Diethylamino)ethyl Aspirin10 20 30 acetylsalicylate hydrochloride (RS)-N-[1-(1-Benzothien-2-Zileuton 10 20 30 yl)ethyl]-N-(2- diethylaminoacetyloxy)ureahydrochloride Vardenafil•HCl N/A 1.5 3 4.5 (Isopropyl(±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30 (hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl benzeneacetate hydrochloride

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 11.1.

TABLE 11.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  148 ± 24*  312 ± 61  189 ± 23*  155± 22*  149 ± 21* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −34.1 ± 3.1* −64.5 ± 2.8 −49.2 ± 2.5* −41.0 ± 2.9*−34.7 ± 2.7* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 11.2.

TABLE 11.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.041 ± 0.011* 0.551 ± 0.123 0.198 ± 0.035 0.111 ± 0.015* 0.057± 0.017* in Blood (×10⁶/mL) Neutrophil Number 0.55 ± 0.14* 1.17 ± 0.17 0.76 ± 0.17* 0.63 ± 0.15* 0.53 ± 0.18* in Blood (×10⁶/mL) Mononuclearcell 2.25 ± 0.16  5.29 ± 0.19 2.88 ± 0.55 1.87 ± 0.23* 1.48 ± 0.26*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.35 ± 0.06* 1.81 ± 0.18 0.87 ± 0.24* 0.53 ± 0.15* 0.41 ± 0.11* in BALF (×10⁶/mL) NeutrophilNumber 0.31 ± 0.15* 0.58 ± 0.19  0.43 ± 0.12* 0.39 ± 0.13* 0.33 ± 0.13*in BALF (×10⁶/mL) Mononuclear cell 0.28 ± 0.08* 1.12 ± 0.20 0.67 ± 0.250.46 ± 0.16* 0.38 ± 0.11* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table11.3.

TABLE 11.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5(pg/mg of 0.34 ± 0.16* 1.03 ± 0.15 0.67 ±0.18* 0.51 ± 0.17* 0.43 ± 0.11* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 27. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), 2-(diethylamino)ethyl acetylsalicylate hydrochloride(10 mg/kg, 2% solution in 25% ethanol/water), tadalafil hydrochloride(1.5 mg/kg, 0.5% solution in 25% ethanol/water), 2-(diethylamino)ethyl2-[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (1.5 mg/kg, 0.5% solution in 25% ethanol/water) and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(1.5 mg/kg, 0.3% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), 2-(diethylamino)ethyl acetylsalicylate hydrochloride(20 mg/kg, 4% solution in 25% ethanol/water), tadalafil hydrochloride (3mg/kg, 1% solution in 25% ethanol/water), 2-(diethylamino)ethyl2-[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (3 mg/kg, 1% solution in 25% ethanol/water) and (isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(3 mg/kg, 0.6% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), 2-(diethylamino)ethyl acetylsalicylate hydrochloride(30 mg/kg, 6% solution in 25% ethanol/water), tadalafil hydrochloride(145 mg/kg, 1.5% solution in 25% ethanol/water), 2-(diethylamino)ethyl2-[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (4.5 mg/kg, 1.5% solution in 25% ethanol/water) and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(4.5 mg/kg, 0.9% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 12.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 12 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug DoseDose Dose (mg/kg) (mg/kg) (mg/kg) Group No. HPP Parent drug 3 4 53-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8- Cefoxitin 10 20 30oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- (diethylamino)ethylester hydrochloride 2-(diethylamino)ethyl acetylsalicylate Aspirin 10 2030 hydrochloride tadalafil hydrochloride N/A 1.5 3 4.52-(diethylamino)ethyl 2-[R-(E)]-1-[[[1-[3-[2-(7- Montelukast 1.5 3 4.5chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1- hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopro- paneacetatehydrochloride (isopropyl (E)-3-{6-[(E)-1-(4-methylphenyl)-3- Acrivastine1.5 3 4.5 pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2- enoate)

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 12.1.

TABLE 12.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  153 ± 21*  319 ± 62  212 ± 20*  167± 23*  159 ± 18* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −32.6 ± 3.1* −62.5 ± 2.9 −49.2 ± 2.1* −41.0 ± 2.4*−33.9 ± 2.8* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 12.2.

TABLE 12.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.043 ± 0.015* 0.556 ± 0.127 0.199 ± 0.025 0.120 ± 0.017* 0.053± 0.016* in Blood (×10⁶/mL) Neutrophil Number 0.52 ± 0.15* 1.09 ± 0.18 0.72 ± 0.19* 0.65 ± 0.13* 0.53 ± 0.17* in Blood (×10⁶/mL) Mononuclearcell 2.17 ± 0.19  5.01 ± 0.19 2.99 ± 0.51 1.66 ± 0.24* 1.53 ± 0.28*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.32 ± 0.06* 1.89 ± 0.17 0.71 ± 0.23* 0.62 ± 0.13* 0.44 ± 0.11* in BALF (×10⁶/mL) NeutrophilNumber 0.30 ± 0.15* 0.61 ± 0.17  0.42 ± 0.14* 0.39 ± 0.17* 0.34 ± 0.15*in BALF (×10⁶/mL) Mononuclear cell 0.28 ± 0.08* 1.11 ± 0.18 0.61 ± 0.210.44 ± 0.15* 0.39 ± 0.11* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table12.3.

TABLE 12.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5 (pg/mg of 0.37 ± 0.13* 1.07 ± 0.15 0.69 ±0.17* 0.52 ± 0.13* 0.41 ± 0.09* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 28. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (10 mg/kg, 2% solution in25% ethanol/water), 2-(diethylamino)ethyl 2-(ρ-isobutylphenyl)propionate hydrochloride (5 mg/kg, 1% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (1 mg/kg, 0.3% solution in 25% ethanol/water), udenafilhydrochloride (3 mg/kg, 1% solution in 25% ethanol/water), and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(1.5 mg/kg, 0.3% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 14 to day 22.

In group 4, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (20 mg/kg, 4% solution in25% ethanol/water), 2-(diethylamino)ethyl 2-(ρ-isobutylphenyl)propionate hydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (2 mg/kg, 0.6% solution in 25% ethanol/water), udenafilhydrochloride (6 mg/kg, 2% solution in 25% ethanol/water), and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(3 mg/kg, 0.6% solution in 25% ethanol/water) to the shaved skin on theneck once per day from day 15 to 22.

In group 5, each mouse was applied with a combination of3-[[(aminocarbonyl)oxy]methyl]-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid 2-(diethylamino)ethyl ester hydrochloride (30 mg/kg, 6% solution in25% ethanol/water), 2-(diethylamino)ethyl 2-(ρ-isobutylphenyl)propionate hydrochloride (15 mg/kg, 3% solution in 25% ethanol/water),diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride (3 mg/kg, 0.9% solution in 25% ethanol/water), udenafilhydrochloride (9 mg/kg, 3% solution in 25% ethanol/water), and(isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3-pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2-enoate)(4.5 mg/kg, 0.9% solution in 25% ethanol/water) to the shaved skin onthe neck once per day from day 15 to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 13.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 13 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Parent DoseDose Dose HPP/Drug drug (mg/kg) (mg/kg) (mg/kg) Group No. 3 4 53-[[(Aminocarbonyl)oxy]methyl]-7-methoxy-8- Cefoxitin 10 20 30oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2- (diethylamino)ethylester hydrochloride 2-(Diethylamino)ethyl 2-(ρ-isobutylphenyl) Ibuprofen5 10 15 propionate hydrochloride Diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro- Montelukast 1 2 32-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate hydrochlorideudenafil hydrochloride N/A 3 6 9 (Isopropyl(E)-3-{6-[(E)-1-(4-methylphenyl)-3- Acrivastine 1.5 3 4.5pyrrolidine-1-yl-prop-1-enyl]pyridin-2-yl}prop-2- enoate)

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 13.1.

TABLE 13.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  149 ± 21*  307 ± 63  211 ± 23*  187± 21*  152 ± 19* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −32.7 ± 3.0* −65.1 ± 3.4 −49.2 ± 2.1* −41.6 ± 2.7*−35.1 ± 2.6* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 13.2.

TABLE 13.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.039 ± 0.011* 0.527 ± 0.127 0.191 ± 0.031 0.123 ± 0.016* 0.056± 0.016* in Blood (×10⁶/mL) Neutrophil Number 0.52 ± 0.14* 1.11 ± 0.18 0.71 ± 0.17* 0.64 ± 0.13* 0.45 ± 0.16* in Blood (×10⁶/mL) Mononuclearcell 1.92 ± 0.17  5.11 ± 0.18 2.73 ± 0.49 1.97 ± 0.21* 1.62 ± 0.24*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.30 ± 0.06* 1.81 ± 0.14 0.62 ± 0.23* 0.51 ± 0.16* 0.39 ± 0.09* in BALF (×10⁶/mL) NeutrophilNumber 0.34 ± 0.14* 0.63 ± 0.18  0.49 ± 0.16* 0.41 ± 0.17* 0.35 ± 0.16*in BALF (×10⁶/mL) Mononuclear cell 0.31 ± 0.09* 1.11 ± 0.24 0.64 ± 0.210.51 ± 0.15* 0.39 ± 0.13* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table13.3.

TABLE 13.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5 (pg/mg of 0.39 ± 0.16* 1.11 ± 0.14 0.65 ±0.16* 0.49 ± 0.12* 0.42 ± 0.10* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 29. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (5mg/kg, 1% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (10 mg/kg, 2% solution in 25% ethanol/water), sildenafilcitrate (3 mg/kg, 0.6% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (10 mg/kg, 2% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 14to day 22.

In group 4, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (10mg/kg, 2% solution in 25% ethanol/water),RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 4% solution in 25% ethanol/water), sildenafilcitrate (6 mg/kg, 1.2% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (15mg/kg, 3% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water), sildenafilcitrate (9 mg/kg, 1.8% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 14.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 14 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug DoseDose Dose (mg/ (mg/ (mg/ HPP Parent drug kg) kg) kg) Group No. 3 4 5 6-Penicilin V 10 20 30 Phenoxyacetacetamidopenicillanic acid2-diethylaminoethyl ester hydrochloride 2-(Diethylamino)ethyl 2-(ρ-Ibuprofen 5 10 15 isobutylphenyl) propionate hydrochloride (RS) -N-[1-(1-Benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride Sildenafil citrate N/A 3 6 9Isopropyl (±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30(hydroxydiphenylmethyl)-1- piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 14.1.

TABLE 14.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  147 ± 24*  301 ± 60 197 ± 23*  171± 18*  152 ± 19* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −32.4 ± 3.0* −64.1 ± 3.0 49.1 ± 2.1* −41.0 ± 2.7*−37.1 ± 2.1* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 14.2.

TABLE 14.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.042 ± 0.011* 0.511 ± 0.117 0.193 ± 0.031 0.115 ± 0.016* 0.057± 0.016* in Blood (×10⁶/mL) Neutrophil Number 0.53 ± 0.14* 1.11 ± 0.19 0.73 ± 0.19* 0.61 ± 0.13* 0.49 ± 0.11* in Blood (×10⁶/mL) Mononuclearcell 2.01 ± 0.17  5.11 ± 0.14 2.89 ± 0.45 1.77 ± 0.25* 1.52 ± 0.29*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.33 ± 0.07* 1.81 ± 0.17 0.79 ± 0.27* 0.49 ± 0.17* 0.39 ± 0.14* in BALF (×10⁶/mL) NeutrophilNumber 0.31 ± 0.18* 0.61 ± 0.17  0.49 ± 0.18* 0.46 ± 0.17* 0.38 ± 0.17*in BALF (×10⁶/mL) Mononuclear cell 0.32 ± 0.09* 1.11 ± 0.20 0.64 ± 0.220.49 ± 0.11* 0.41 ± 0.14* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table

TABLE 14.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5 pg/mg of 0.41 ± 0.16* 1.01 ± 0.11 0.65 ±0.17* 0.55 ± 0.16* 0.45 ± 0.15* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

Example 30. Animal Test of Drug Combinations Disclosed Herein

Experiments similar to those described in Example 16 were performed. 48female, BALB/c mice between 4 and 6 weeks of age were prepared andgrouped as described in Example 16. Groups 1 and 2 were treated the sameas described in Example 16.

In group 3, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (10 mg/kg, 2% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (5mg/kg, 1% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (10 mg/kg, 2% solution in 25% ethanol/water), vardenafilhydrochloride (3 mg/kg, 0.6% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (10 mg/kg, 2% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 14to day 22.

In group 4, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (20 mg/kg, 4% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (10mg/kg, 2% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (20 mg/kg, 4% solution in 25% ethanol/water), vardenafilhydrochloride (6 mg/kg, 1.2% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (20 mg/kg, 4% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

In group 5, each mouse was applied with a combination of6-phenoxyacetacetamidopenicillanic acid 2-diethylaminoethyl esterhydrochloride (30 mg/kg, 6% solution in 25% ethanol/water),2-(diethylamino)ethyl 2-(ρ-isobutylphenyl) propionate hydrochloride (15mg/kg, 3% solution in 25% ethanol/water),(RS)—N-[1-(1-benzothien-2-yl)ethyl]-N-(2-diethylaminoacetyloxyl)ureahydrochloride (30 mg/kg, 6% solution in 25% ethanol/water), vardenafilhydrochloride (9 mg/kg, 2% solution in 25% ethanol/water) andisopropyl(±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride (30 mg/kg, 6% solution in 25%ethanol/water) to the shaved skin on the neck once per day from day 15to 22.

The doses of HPPs and drug applied to Groups 3, 4, and 5 are summarizedin Table 15.

When applying a combination of a plurality of drugs (e.g. one or moreHPPs and/or other drug(s)) to a subject, each drug could be appliedseparately, or one or more of the drugs could be applied at the sametime as separate drugs (e.g. spraying two or more drugs at substantiallythe same time without mixing the drugs before spraying), or one or moredrugs could be mixed together before applying to the subject, or anycombination of the above application methods. The drugs could be appliedin any order possible.

TABLE 15 Doses of HPPs/Drugs applied to Groups 3, 4, and 5 Drug DoseDose Dose (mg/ (mg/ (mg/ HPP Parent drug kg) kg) kg) Group No. 3 4 5 6-Penicilin V 10 20 30 Phenoxyacetacetamidopenicillanic acid2-diethylaminoethyl ester hydrochloride 2-(Diethylamino)ethyl 2-(p-Ibuprofen 5 10 15 isobutylphenyl) propionate hydrochloride (RS) -N-[1-(1-benzothien-2- Zileuton 10 20 30 yl)ethyl]-N-(2-diethylaminoacetyloxy)urea hydrochloride Vardenafil hydrochloride N/A 36 9 Isopropyl (±)-4-[1-hydroxy-4-[4- Fexofenadine 10 20 30(hydroxydiphenylmethyl)-1- piperidinyl]-butyl]-α,α-dimethylbenzeneacetate hydrochloride

Airway responsiveness [transpulmonary resistance (R_(L)) and dynamiccompliance (C_(dyn))] to inhaled β-methacholine were determinedfollowing the same protocol as described in Example 16. The results areshown in Table 15.1.

TABLE 15.1 Airway Hyperresponsiveness Naïve Vehicle Low dose Middle doseHigh dose Transpulmonary resistance  149 ± 26*  301 ± 62  215 ± 19*  181± 21*  148 ± 19* (percent of saline control at 25 mg/ml methacholine)Dynamic compliance −33.5 ± 3.1* −64.5 ± 3.0 −48.9 ± 2.1* −39.9 ± 2.2*−35.9 ± 2.5* (percent of saline control at 25 mg/ml methacholine) *P <0.001, significant difference compared with vehicle-treated animals

Eosinophil numbers, neutrophil number and mononuclear cell numbers inBALF were determined following the same protocol as described in Example16. The results are shown in Table 15.2.

TABLE 15.2 Eosinophil numbers, neutrophil number and mononuclear cellnumbers in BALF Naïve Vehicle Low dose Middle dose High dose EosinophilNumbers 0.050 ± 0.011* 0.517 ± 0.141 0.196 ± 0.026 0.115 ± 0.017* 0.053± 0.017* in Blood (×10⁶/mL) Neutrophil Number 0.49 ± 0.14* 1.11 ± 0.17 0.75 ± 0.19* 0.63 ± 0.13* 0.47 ± 0.17* in Blood (×10⁶/mL) Mononuclearcell 2.26 ± 0.17  5.01 ± 0.18 2.71 ± 0.42 1.55 ± 0.21* 1.34 ± 0.21*numbers in Blood (×10⁶/mL) Eosinophil Numbers 0.30 ± 0.07* 1.89 ± 0.18 0.71 ± 0.25* 0.49 ± 0.18* 0.38 ± 0.13* in BALF (×10⁶/mL) NeutrophilNumber 0.30 ± 0.15* 0.56 ± 0.17  0.41 ± 0.15* 0.38 ± 0.17* 0.32 ± 0.15*in BALF (×10⁶/mL) Mononuclear cell 0.28 ± 0.07* 1.17 ± 0.20 0.71 ± 0.250.51 ± 0.17* 0.37 ± 0.13* numbers in BALF (×10⁶/mL) *P < 0.001,significant difference compared with vehicle animals.

IL-5 in lung homogenates of animals were determined following the sameprotocol as described in Example 16. The results are shown in Table15.3.

TABLE 15.3 IL-5 in lung homogenates of animals Naïve Vehicle Low doseMiddle dose High dose IL-5 (pg/mg of 0.34 ± 0.13* 1.01 ± 0.15 0.66 ±0.16* 0.47 ± 0.15* 0.37 ± 0.13* tissue) *P < 0.001, significantdifference compared with vehicle animals.

The results of this study show that the test drug combinations hadstrong anti-inflammatory and anti-asthma activities.

What is claimed is:
 1. A topical pharmaceutical formulation comprising apharmaceutically acceptable carrier and a compound of Structure LRA-1:

wherein X₅ is selected from nothing, C(═O), OC(═O), CH₂, O, and NR₅; Y₁,Y₂, Y₃, Y₄, Y₅, Y₆, Y₇, and Y₈ are each independently selected from H,OH, OW, OC(═O)W, OC(═O)CH₃, CH₂OR₆, CH₂C(═O)OR₅, OR₆, CF₃, OCF₃,CH₂(CH₂)_(n)OR₆, F, Br, I, Cl, C(═O)R₅, (CH₃)₂C(OR₆)—, CH₃CH(OH)—,(CH₃)₂CH—, CH₃CH₂—, substituted and unsubstituted C₁-C₃₀ alkyl,substituted and unsubstituted C₁-C₃₀ alkoxyl, and substituted andunsubstituted C₁-C₃₀ alkylamino, wherein n is an integer selected from 1to 10; R₅ is selected from H, OR₆, CH₂CH₂OR₆, CH₂CH₂N(CH₃)₂,CH₂CH₂N(CH₂CH₃)₂, Cl, F, Br, I, substituted and unsubstituted C₁-C₃₀alkyl, substituted and unsubstituted C₃-C₃₀ cycloalkyl, substituted andunsubstituted C₃-C₃₀ heterocycloalkyl, substituted and unsubstitutedC₁-C₃₀ alkyloxyl, substituted and unsubstituted C₃-C₃₀ cycloalkyloxyl,substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl, substituted and unsubstituted C₁-C₃₀ alkylcarbonyl,substituted and unsubstituted C₁-C₃₀ alkylamino, L₁-L₄-L₂-W, andC—(═O)-W; R₆ is selected from H, F, Cl, Br, I, C(═O)R₅, substituted andunsubstituted C₁-C₃₀ alkyl, substituted and unsubstituted C₃-C₃₀cycloalkyl, substituted and unsubstituted C₃-C₃₀ heterocycloalkyl,substituted and unsubstituted C₂-C₃₀ alkenyl, substituted andunsubstituted C₂-C₃₀ alkynyl, substituted and unsubstituted C₁-C₃₀alkyloxyl, substituted and unsubstituted C₃-C₃₀ cycloalkyloxyl,substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl, L₁-L₄-L₂-W, and C—(═O)-W; R is selected from nothing,CH₂C(═O)OR₆, substituted and unsubstituted C₁-C₃₀ alkylene, substitutedand unsubstituted C₃-C₃₀ cycloalkylene, substituted and unsubstitutedC₃-C₃₀ heterocycloalkylene, substituted and unsubstituted C₁-C₃₀alkoxylene, substituted and unsubstituted C₂-C₃₀ alkenylene, substitutedand unsubstituted C₂-C₃₀ alkynylene, substituted and unsubstituted aryl,and substituted and unsubstituted heteroaryl, wherein any CH₂ in R maybe further replaced with O, S, or NR₆; R₁ and R₂ are each independentlyselected from H, substituted and unsubstituted C₁-C₃₀ alkyl, substitutedand unsubstituted C₃-C₃₀ cycloalkyl, substituted and unsubstitutedC₃-C₃₀ heterocycloalkyl, substituted and unsubstituted C₁-C₃₀ alkyloxyl,substituted and unsubstituted C₂-C₃₀ alkenyl, substituted andunsubstituted C₂-C₃₀ alkynyl, substituted and unsubstituted aryl andsubstituted and unsubstituted heteroaryl residues, wherein any CH₂group(s) may be replaced with O, S, or NH; R₁₁ and R₁₂ are eachindependently selected from nothing, H, CH₂C(═O)OR₁₁, substituted andunsubstituted C₁-C₃₀ alkylene, substituted and unsubstituted C₃-C₃₀cycloalkylene, substituted and unsubstituted C₃-C₃₀ heterocycloalkylene,substituted and unsubstituted C₁-C₃₀ alkoxylene, substituted andunsubstituted C₂-C₃₀ alkenylene, substituted and unsubstituted C₂-C₃₀alkynylene, substituted and unsubstituted aryl, and substituted andunsubstituted heteroaryl, wherein any CH₂ group(s) may be replaced withO, S, or NH; L₁ and L₂ are each independently selected from nothing, O,—O-L₃-, —N(L₃)-, —N(L₃)-CH₂—O, —N(L₃)-CH₂—N(L₅)-, —O—CH₂—O—, and—O—CH(L₃)-O, wherein for each of L₁ and L₂, each of L₃ and L₅ isindependently selected from nothing, H, substituted and unsubstitutedC₁-C₃₀ alkyl, substituted and unsubstituted C₃-C₃₀ cycloalkyl,substituted and unsubstituted C₃-C₃₀ heterocycloalkyl, substituted andunsubstituted aryl, substituted and unsubstituted heteroaryl,substituted and unsubstituted C₁-C₃₀ alkoxyl, substituted andunsubstituted C₁-C₃₀ alkylamino, wherein any carbon or hydrogen may befurther independently replaced with O, S, or NL₃; L₄ is selected fromnothing and C═O; W is selected from Structure W-1 and Structure W-2:

HA is selected from nothing, hydrochloride, hydrobromide, hydroiodide,nitric acid, sulfic acid, bisulfic acid, phosphoric acid, phosphorousacid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid,salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaricacid, ascorbic acid, succinic acid, maleic acid, or any otherpharmaceutically acceptable acid.
 2. The topical pharmaceuticalformulation of claim 1, wherein W is Structure W-1.
 3. The topicalpharmaceutical formulation of claim 1, wherein the compound of StructureLRA-1 is selected from diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetate;diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate;2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate;and pharmaceutically acceptable salts thereof.
 4. The topicalpharmaceutical formulation of claim 3, wherein the compound of StructureLRA-1 is selected from diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride; diethylaminoethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride; and 2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride.
 5. The topical pharmaceutical formulation of claim 1,which is a solution that can be sprayed onto skin of a patient.
 6. Thetopical pharmaceutical formulation of claim 5, wherein the compound ofStructure LRA-1 is diethylaminoethyl[R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetatehydrochloride.
 7. The topical pharmaceutical formulation of claim 5,wherein the compound of Structure LRA-1 is 2-pyrrolidinemethyl2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetatehydrochloride.
 8. The topical pharmaceutical formulation of claim 5,which is an aqueous solution optionally comprising an alcohol.